Article

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

To the Editor:

Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.¹ Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.² In 2020, Smirnova et al³ reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.⁴

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).

Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).

Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.⁵ Additionally, Harazin et al⁶ discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.⁶

Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.

To the Editor:

Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.¹ Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.² In 2020, Smirnova et al³ reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.⁴

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).

Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).

Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.⁵ Additionally, Harazin et al⁶ discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.⁶

Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.

To the Editor:

Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.¹ Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.² In 2020, Smirnova et al³ reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.⁴

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).

Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).

Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.⁵ Additionally, Harazin et al⁶ discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.⁶

Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.^1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.^3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.⁶ The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,^7,8 nutritional deficiencies,^4,9 and/or major surgery.¹⁰

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.¹¹ Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.¹² This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.¹² First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.^13,14 Retinoids modulate sebum production,¹⁵ keratinocyte proliferation,¹⁶ and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.^13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,¹⁸ psoriasis,¹⁹ and ichthyosis.²⁰ The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.²¹ Retinoid-associated alopecia is dose and duration dependent.^19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.²³ A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.²⁴ In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m² alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.²⁵ In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.²⁶ Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.^14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.²⁸ Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.²⁹ A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.³⁰ The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.³⁰ Fluconazole-induced TE was reproducible in an animal model using Wistar rats³¹; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.³² Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.³² Voriconazole and fluconazole share structural similarity not present with other triazoles.^33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.³¹

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.^35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.³⁷ A systemic review and meta-analysis by Wang et al³⁸ estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,³⁸ a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.³⁹ A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).⁴⁰ Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.^41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,⁴³ and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.⁴¹ Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.^44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.⁴⁴ In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.⁴⁵ Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).⁴⁶ Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.^39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.⁴⁸ Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.⁴⁹ A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.⁵⁰ The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study⁴⁰ and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.⁵¹ Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.⁵² Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use⁵³; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).⁵⁴

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors^55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.⁵⁷ Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.^58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.⁶³ A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.⁶⁴ Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.⁶⁴ Several other case reports have described alopecia following treatment with SSRIs, including sertraline,⁶⁵ fluvoxamine,⁶⁶ paroxetine,⁶⁷ fluoxetine,⁶⁸ and escitalopram.⁶⁹

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.^1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.^3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.⁶ The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,^7,8 nutritional deficiencies,^4,9 and/or major surgery.¹⁰

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.¹¹ Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.¹² This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.¹² First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.^13,14 Retinoids modulate sebum production,¹⁵ keratinocyte proliferation,¹⁶ and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.^13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,¹⁸ psoriasis,¹⁹ and ichthyosis.²⁰ The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.²¹ Retinoid-associated alopecia is dose and duration dependent.^19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.²³ A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.²⁴ In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m² alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.²⁵ In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.²⁶ Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.^14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.²⁸ Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.²⁹ A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.³⁰ The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.³⁰ Fluconazole-induced TE was reproducible in an animal model using Wistar rats³¹; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.³² Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.³² Voriconazole and fluconazole share structural similarity not present with other triazoles.^33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.³¹

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.^35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.³⁷ A systemic review and meta-analysis by Wang et al³⁸ estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,³⁸ a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.³⁹ A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).⁴⁰ Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.^41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,⁴³ and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.⁴¹ Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.^44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.⁴⁴ In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.⁴⁵ Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).⁴⁶ Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.^39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.⁴⁸ Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.⁴⁹ A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.⁵⁰ The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study⁴⁰ and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.⁵¹ Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.⁵² Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use⁵³; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).⁵⁴

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors^55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.⁵⁷ Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.^58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.⁶³ A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.⁶⁴ Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.⁶⁴ Several other case reports have described alopecia following treatment with SSRIs, including sertraline,⁶⁵ fluvoxamine,⁶⁶ paroxetine,⁶⁷ fluoxetine,⁶⁸ and escitalopram.⁶⁹

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.^1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.^3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.⁶ The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,^7,8 nutritional deficiencies,^4,9 and/or major surgery.¹⁰

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.¹¹ Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.¹² This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.¹² First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.^13,14 Retinoids modulate sebum production,¹⁵ keratinocyte proliferation,¹⁶ and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.^13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,¹⁸ psoriasis,¹⁹ and ichthyosis.²⁰ The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.²¹ Retinoid-associated alopecia is dose and duration dependent.^19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.²³ A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.²⁴ In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m² alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.²⁵ In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.²⁶ Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.^14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.²⁸ Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.²⁹ A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.³⁰ The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.³⁰ Fluconazole-induced TE was reproducible in an animal model using Wistar rats³¹; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.³² Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.³² Voriconazole and fluconazole share structural similarity not present with other triazoles.^33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.³¹

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.^35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.³⁷ A systemic review and meta-analysis by Wang et al³⁸ estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,³⁸ a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.³⁹ A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).⁴⁰ Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.^41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,⁴³ and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.⁴¹ Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.^44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.⁴⁴ In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.⁴⁵ Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).⁴⁶ Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.^39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.⁴⁸ Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.⁴⁹ A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.⁵⁰ The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study⁴⁰ and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.⁵¹ Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.⁵² Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use⁵³; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).⁵⁴

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors^55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.⁵⁷ Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.^58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.⁶³ A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.⁶⁴ Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.⁶⁴ Several other case reports have described alopecia following treatment with SSRIs, including sertraline,⁶⁵ fluvoxamine,⁶⁶ paroxetine,⁶⁷ fluoxetine,⁶⁸ and escitalopram.⁶⁹

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.¹ In the United States, Black patients are 3.4-times more likely than White patients to have PN.² The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.

Treatment Guidelines

In 2020, an expert panel published consensus treatment guidelines for PN.¹ The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.¹

FDA-Approved Therapy

In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.³ Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.³

The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.^4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.⁶

Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.⁷ In a recent review of 701 patients with PN, the mean age was 64.8 years,⁵ highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.

Investigation of Janus Kinase Inhibitors

Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.^8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.¹⁰ Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.¹¹ The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.

Other New Therapies

Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.^12,13 Sustained remission was noted even after discontinuation of the medication.¹² Alitretinoin, which has been demonstrated to be effective in treating dermatitis,¹⁴ was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.

Topical cannabinoids have shown benefit in the treatment of pruritus¹⁵ and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.

Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.¹⁶ Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.¹⁷ Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.¹⁸

Final Thoughts

Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.

Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.¹ In the United States, Black patients are 3.4-times more likely than White patients to have PN.² The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.

Treatment Guidelines

In 2020, an expert panel published consensus treatment guidelines for PN.¹ The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.¹

FDA-Approved Therapy

In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.³ Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.³

The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.^4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.⁶

Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.⁷ In a recent review of 701 patients with PN, the mean age was 64.8 years,⁵ highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.

Investigation of Janus Kinase Inhibitors

Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.^8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.¹⁰ Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.¹¹ The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.

Other New Therapies

Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.^12,13 Sustained remission was noted even after discontinuation of the medication.¹² Alitretinoin, which has been demonstrated to be effective in treating dermatitis,¹⁴ was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.

Topical cannabinoids have shown benefit in the treatment of pruritus¹⁵ and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.

Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.¹⁶ Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.¹⁷ Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.¹⁸

Final Thoughts

Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.

Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.¹ In the United States, Black patients are 3.4-times more likely than White patients to have PN.² The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.

Treatment Guidelines

In 2020, an expert panel published consensus treatment guidelines for PN.¹ The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.¹

FDA-Approved Therapy

In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.³ Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.³

The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.^4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.⁶

Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.⁷ In a recent review of 701 patients with PN, the mean age was 64.8 years,⁵ highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.

Investigation of Janus Kinase Inhibitors

Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.^8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.¹⁰ Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.¹¹ The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.

Other New Therapies

Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.^12,13 Sustained remission was noted even after discontinuation of the medication.¹² Alitretinoin, which has been demonstrated to be effective in treating dermatitis,¹⁴ was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.

Topical cannabinoids have shown benefit in the treatment of pruritus¹⁵ and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.

Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.¹⁶ Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.¹⁷ Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.¹⁸

Final Thoughts

Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.

Practice Gap

In low-resource settings, dermatologists may not have the preferred tools to evaluate a patient or perform a procedure. Commonplace affordable supplies can be substituted when needed.

Traditionally, tools readily available for comedone extraction in dermatology clinics include sterile disposable hypodermic needles to open the skin and either a comedone extractor or 2 cotton-tip applicators to apply pressure for extraction. However, when these tools are not available, resourceful techniques have been utilized. Ashique and Srinivas¹ described a less-painful method for extracting conchae comedones that they called “pen punching,” which involved using the rim of the tip of a ballpoint pen to apply pressure to extract lesions. Mukhtar and Gupta² used a 3-mL disposable syringe as a comedone extractor; the syringe was cut at the needle hub using a surgical blade, with one half at 30° to 45°. Kaya et al³ used sharp-tipped cautery to puncture closed macrocomedones. Cvancara and Meffert⁴ described how an autoclaved paper clip could be fashioned into a disposable comedone extractor, highlighting its potential use in humanitarian work or military deployments. A sterilized safety pin has been demonstrated to be an inexpensive tool to extract open and closed comedones without a surgical blade.⁵ We describe the use of a blood glucose testing lancet and a paper clip for comedone extraction.

Tools and Technique

A patient presented to a satellite clinic requesting extraction of multiple bothersome milia. A comedone extractor was unavailable at that location, and the patient’s access to care elsewhere was limited.

To perform extraction of milia in this case, we used a sterile, twist-top, stainless steel, 30-gauge blood glucose testing lancet and a paper clip sterilized with an isopropyl alcohol wipe (Figure). The beveled edge of the lancet was used to make a superficial opening to the skin, and the end loop of the paper clip was used as a comedone extractor. Applying moderate vertical pressure, 15 milia were expressed from the forearms. The patient tolerated the procedure well and reported minimal pain.

Practical Implications

The cost of the paper clip and lancet for our technique was $0.07. These materials are affordable, easy to use, and readily found in a variety of settings, making them a feasible option for performing this procedure. 

Practice Gap

In low-resource settings, dermatologists may not have the preferred tools to evaluate a patient or perform a procedure. Commonplace affordable supplies can be substituted when needed.

Traditionally, tools readily available for comedone extraction in dermatology clinics include sterile disposable hypodermic needles to open the skin and either a comedone extractor or 2 cotton-tip applicators to apply pressure for extraction. However, when these tools are not available, resourceful techniques have been utilized. Ashique and Srinivas¹ described a less-painful method for extracting conchae comedones that they called “pen punching,” which involved using the rim of the tip of a ballpoint pen to apply pressure to extract lesions. Mukhtar and Gupta² used a 3-mL disposable syringe as a comedone extractor; the syringe was cut at the needle hub using a surgical blade, with one half at 30° to 45°. Kaya et al³ used sharp-tipped cautery to puncture closed macrocomedones. Cvancara and Meffert⁴ described how an autoclaved paper clip could be fashioned into a disposable comedone extractor, highlighting its potential use in humanitarian work or military deployments. A sterilized safety pin has been demonstrated to be an inexpensive tool to extract open and closed comedones without a surgical blade.⁵ We describe the use of a blood glucose testing lancet and a paper clip for comedone extraction.

Tools and Technique

A patient presented to a satellite clinic requesting extraction of multiple bothersome milia. A comedone extractor was unavailable at that location, and the patient’s access to care elsewhere was limited.

To perform extraction of milia in this case, we used a sterile, twist-top, stainless steel, 30-gauge blood glucose testing lancet and a paper clip sterilized with an isopropyl alcohol wipe (Figure). The beveled edge of the lancet was used to make a superficial opening to the skin, and the end loop of the paper clip was used as a comedone extractor. Applying moderate vertical pressure, 15 milia were expressed from the forearms. The patient tolerated the procedure well and reported minimal pain.

Practical Implications

The cost of the paper clip and lancet for our technique was $0.07. These materials are affordable, easy to use, and readily found in a variety of settings, making them a feasible option for performing this procedure. 

Practice Gap

In low-resource settings, dermatologists may not have the preferred tools to evaluate a patient or perform a procedure. Commonplace affordable supplies can be substituted when needed.

Traditionally, tools readily available for comedone extraction in dermatology clinics include sterile disposable hypodermic needles to open the skin and either a comedone extractor or 2 cotton-tip applicators to apply pressure for extraction. However, when these tools are not available, resourceful techniques have been utilized. Ashique and Srinivas¹ described a less-painful method for extracting conchae comedones that they called “pen punching,” which involved using the rim of the tip of a ballpoint pen to apply pressure to extract lesions. Mukhtar and Gupta² used a 3-mL disposable syringe as a comedone extractor; the syringe was cut at the needle hub using a surgical blade, with one half at 30° to 45°. Kaya et al³ used sharp-tipped cautery to puncture closed macrocomedones. Cvancara and Meffert⁴ described how an autoclaved paper clip could be fashioned into a disposable comedone extractor, highlighting its potential use in humanitarian work or military deployments. A sterilized safety pin has been demonstrated to be an inexpensive tool to extract open and closed comedones without a surgical blade.⁵ We describe the use of a blood glucose testing lancet and a paper clip for comedone extraction.

Tools and Technique

A patient presented to a satellite clinic requesting extraction of multiple bothersome milia. A comedone extractor was unavailable at that location, and the patient’s access to care elsewhere was limited.

To perform extraction of milia in this case, we used a sterile, twist-top, stainless steel, 30-gauge blood glucose testing lancet and a paper clip sterilized with an isopropyl alcohol wipe (Figure). The beveled edge of the lancet was used to make a superficial opening to the skin, and the end loop of the paper clip was used as a comedone extractor. Applying moderate vertical pressure, 15 milia were expressed from the forearms. The patient tolerated the procedure well and reported minimal pain.

Practical Implications

The cost of the paper clip and lancet for our technique was $0.07. These materials are affordable, easy to use, and readily found in a variety of settings, making them a feasible option for performing this procedure. 

The Diagnosis: Giant Acrochordon

Based on the clinical and histologic findings, our patient was diagnosed with a giant acrochordon. Acrochordons (also known as fibroepithelial polyps or skin tags) are among the most commonly identified skin lesions and are believed to affect up to 46% of the general population.^1,2 These benign growths typically appear after middle age in men and women alike and are believed to be of ectodermal and mesenchymal origin.³ The most common locations include the axillae, neck, and inguinal folds. They generally are small, measuring only a few millimeters, and frequently present as multiple lesions that are called giant acrochordons when their size exceeds 5 cm in length.² Acrochordons are benign lesions with only rare reports of the presence of basal or squamous cell carcinoma within the lesion on pathology.⁴ In addition to being cosmetically unsightly, patients with acrochordons often report pruritus. These lesions are easily removed in an outpatient setting via snip excision, cryosurgery, or electrodesiccation. Once removed, recurrence is unlikely. Despite the prevalence of fibroepithelial polyps worldwide, reports of giant acrochordons are limited. The histopathology of giant acrochordons is similar to smaller acrochordons, with features including epidermal acanthosis and a central core of fibrovascular tissue without adnexal structures (Figure).⁴

The differential diagnosis of giant acrochordon includes neurofibroma, nodular melanoma, squamous cell carcinoma, and giant condylomata acuminata (Buschke-Löwenstein tumor).¹ It is important to consider the clinical presentation and histopathologic findings to differentiate giant acrochordons from these other entities.

Neurofibromas typically present as multiple flesh-colored to brown nodules that invaginate into the skin when minimal external pressure is applied.⁵ Histopathology demonstrates a discrete, nonencapsulated, dermal collection of small nerve fibers and loosely arranged spindle cells. In contrast, giant acrochordons typically present as large, fleshcolored, pedunculated, verrucous tumors with a central stalk. Histopathology reveals epidermal acanthosis and a central core of fibrovascular tissue without adnexal structures.

Nodular melanomas usually are blue to black and grow rapidly over the course of several months.⁶ They have signs of hemorrhagic crust, and histopathology reveals atypical melanocytes, frequent mitoses, pleomorphic tumor cells, and irregular clumping of chromatin within the nuclei. Giant acrochordons are flesh colored, benign, and do not have these malignant features.

Squamous cell carcinoma often presents as an erythematous scaly patch or red plaque on sun-exposed areas of the skin.¹ Histopathology of squamous cell carcinoma shows atypical keratinocytes with an invasive growth pattern; giant acrochordon does not show keratinocytic atypia or invasive epidermal growth.

Giant condylomata acuminata (Buschke-Löwenstein tumor) is a locally destructive verrucous plaque that typically appears on the penis but can occur elsewhere in the anogenital region.⁷ Histopathologic features include epidermal hyperplasia, papillomatosis, and koilocytes. In contrast, giant acrochordons typically are located on the buttocks and do not present with these epidermal changes.

Based on the clinical and histologic findings, our patient was diagnosed with a giant acrochordon, a rare variant of the common skin lesion. Excisional removal was critical for both diagnostic and treatment purposes. By considering the clinical presentation and histopathologic features of other conditions in the differential, giant acrochordons can be distinguished from other similar entities. Diagnosis and prompt surgical removal are important for management of these neoplasms and prevention of misdiagnosis.

The Diagnosis: Giant Acrochordon

Based on the clinical and histologic findings, our patient was diagnosed with a giant acrochordon. Acrochordons (also known as fibroepithelial polyps or skin tags) are among the most commonly identified skin lesions and are believed to affect up to 46% of the general population.^1,2 These benign growths typically appear after middle age in men and women alike and are believed to be of ectodermal and mesenchymal origin.³ The most common locations include the axillae, neck, and inguinal folds. They generally are small, measuring only a few millimeters, and frequently present as multiple lesions that are called giant acrochordons when their size exceeds 5 cm in length.² Acrochordons are benign lesions with only rare reports of the presence of basal or squamous cell carcinoma within the lesion on pathology.⁴ In addition to being cosmetically unsightly, patients with acrochordons often report pruritus. These lesions are easily removed in an outpatient setting via snip excision, cryosurgery, or electrodesiccation. Once removed, recurrence is unlikely. Despite the prevalence of fibroepithelial polyps worldwide, reports of giant acrochordons are limited. The histopathology of giant acrochordons is similar to smaller acrochordons, with features including epidermal acanthosis and a central core of fibrovascular tissue without adnexal structures (Figure).⁴

The differential diagnosis of giant acrochordon includes neurofibroma, nodular melanoma, squamous cell carcinoma, and giant condylomata acuminata (Buschke-Löwenstein tumor).¹ It is important to consider the clinical presentation and histopathologic findings to differentiate giant acrochordons from these other entities.

Neurofibromas typically present as multiple flesh-colored to brown nodules that invaginate into the skin when minimal external pressure is applied.⁵ Histopathology demonstrates a discrete, nonencapsulated, dermal collection of small nerve fibers and loosely arranged spindle cells. In contrast, giant acrochordons typically present as large, fleshcolored, pedunculated, verrucous tumors with a central stalk. Histopathology reveals epidermal acanthosis and a central core of fibrovascular tissue without adnexal structures.

Nodular melanomas usually are blue to black and grow rapidly over the course of several months.⁶ They have signs of hemorrhagic crust, and histopathology reveals atypical melanocytes, frequent mitoses, pleomorphic tumor cells, and irregular clumping of chromatin within the nuclei. Giant acrochordons are flesh colored, benign, and do not have these malignant features.

Squamous cell carcinoma often presents as an erythematous scaly patch or red plaque on sun-exposed areas of the skin.¹ Histopathology of squamous cell carcinoma shows atypical keratinocytes with an invasive growth pattern; giant acrochordon does not show keratinocytic atypia or invasive epidermal growth.

Giant condylomata acuminata (Buschke-Löwenstein tumor) is a locally destructive verrucous plaque that typically appears on the penis but can occur elsewhere in the anogenital region.⁷ Histopathologic features include epidermal hyperplasia, papillomatosis, and koilocytes. In contrast, giant acrochordons typically are located on the buttocks and do not present with these epidermal changes.

Based on the clinical and histologic findings, our patient was diagnosed with a giant acrochordon, a rare variant of the common skin lesion. Excisional removal was critical for both diagnostic and treatment purposes. By considering the clinical presentation and histopathologic features of other conditions in the differential, giant acrochordons can be distinguished from other similar entities. Diagnosis and prompt surgical removal are important for management of these neoplasms and prevention of misdiagnosis.

The Diagnosis: Giant Acrochordon

Based on the clinical and histologic findings, our patient was diagnosed with a giant acrochordon. Acrochordons (also known as fibroepithelial polyps or skin tags) are among the most commonly identified skin lesions and are believed to affect up to 46% of the general population.^1,2 These benign growths typically appear after middle age in men and women alike and are believed to be of ectodermal and mesenchymal origin.³ The most common locations include the axillae, neck, and inguinal folds. They generally are small, measuring only a few millimeters, and frequently present as multiple lesions that are called giant acrochordons when their size exceeds 5 cm in length.² Acrochordons are benign lesions with only rare reports of the presence of basal or squamous cell carcinoma within the lesion on pathology.⁴ In addition to being cosmetically unsightly, patients with acrochordons often report pruritus. These lesions are easily removed in an outpatient setting via snip excision, cryosurgery, or electrodesiccation. Once removed, recurrence is unlikely. Despite the prevalence of fibroepithelial polyps worldwide, reports of giant acrochordons are limited. The histopathology of giant acrochordons is similar to smaller acrochordons, with features including epidermal acanthosis and a central core of fibrovascular tissue without adnexal structures (Figure).⁴

The differential diagnosis of giant acrochordon includes neurofibroma, nodular melanoma, squamous cell carcinoma, and giant condylomata acuminata (Buschke-Löwenstein tumor).¹ It is important to consider the clinical presentation and histopathologic findings to differentiate giant acrochordons from these other entities.

Neurofibromas typically present as multiple flesh-colored to brown nodules that invaginate into the skin when minimal external pressure is applied.⁵ Histopathology demonstrates a discrete, nonencapsulated, dermal collection of small nerve fibers and loosely arranged spindle cells. In contrast, giant acrochordons typically present as large, fleshcolored, pedunculated, verrucous tumors with a central stalk. Histopathology reveals epidermal acanthosis and a central core of fibrovascular tissue without adnexal structures.

Nodular melanomas usually are blue to black and grow rapidly over the course of several months.⁶ They have signs of hemorrhagic crust, and histopathology reveals atypical melanocytes, frequent mitoses, pleomorphic tumor cells, and irregular clumping of chromatin within the nuclei. Giant acrochordons are flesh colored, benign, and do not have these malignant features.

Squamous cell carcinoma often presents as an erythematous scaly patch or red plaque on sun-exposed areas of the skin.¹ Histopathology of squamous cell carcinoma shows atypical keratinocytes with an invasive growth pattern; giant acrochordon does not show keratinocytic atypia or invasive epidermal growth.

Giant condylomata acuminata (Buschke-Löwenstein tumor) is a locally destructive verrucous plaque that typically appears on the penis but can occur elsewhere in the anogenital region.⁷ Histopathologic features include epidermal hyperplasia, papillomatosis, and koilocytes. In contrast, giant acrochordons typically are located on the buttocks and do not present with these epidermal changes.

Based on the clinical and histologic findings, our patient was diagnosed with a giant acrochordon, a rare variant of the common skin lesion. Excisional removal was critical for both diagnostic and treatment purposes. By considering the clinical presentation and histopathologic features of other conditions in the differential, giant acrochordons can be distinguished from other similar entities. Diagnosis and prompt surgical removal are important for management of these neoplasms and prevention of misdiagnosis.

With the growing number of treatment options for psoriatic arthritis (PsA), therapeutic decision-making has shifted to an increasingly tailored and patient-centered approach. A number of factors contribute to the treatment decision-making process, including age, insurance restrictions, route of administration, side effect profile, comorbidities, and extra-articular manifestations of the disease. In this article, we discuss an extra-articular comorbidity, uveitis, which is frequently seen in patients with PsA. We discuss clinical characteristics of uveitis associated with PsA and describe how the presence of uveitis influences our treatment approach to PsA, based on existing data.

Uveitis refers broadly to inflammation of the uvea, the vascularized and pigmented layer of the eye composed of the iris, the ciliary body, and the choroid. While infection is a common cause of uveitis, many cases are noninfectious and are often associated with an underlying autoimmune or systemic inflammatory disorder. Uveitis is frequently reported in diseases in the spondyloarthritis (SpA) family, including axial spondyloarthritis (AxSpA) and reactive arthritis, as well as PsA. Exact estimates of the prevalence of uveitis in PsA vary widely from 7%-25%, depending on the particular cohort studied.^1,2 In all forms of SpA, the anterior chamber of the uvea is the most likely to be affected.³ However, compared to patients with AxSpA, patients with PsA appear to have a higher rate of posterior involvement. In addition, patients with PsA appear to have higher frequencies of insidious, bilateral uveitis, as compared to the acute, unilateral, anterior uveitis that is most characteristic of AxSpA.⁴ Women with PsA may be more likely than men to experience uveitis, although this has not been a consistent finding.⁵ 

Patients with PsA who are human leukocyte antigen B27 (HLA-B27) positive may be at risk for more severe and refractory anterior uveitis compared to those who do not express the allele.⁵ Those who are HLA-B27 positive are also known to have higher rates of axial involvement. It has therefore been postulated that 2 phenotypes of uveitis may exist in PsA: patients who are HLA-B27 positive who have axial disease and severe, unilateral anterior uveitis reminiscent of other forms of SpA, and patients who are HLA-B27 negative, often women, with peripheral-predominant arthritis who are prone to the classic anterior uveitis but may also develop atypical bilateral, insidious, and/or posterior involvement.⁴ Specific characteristics of PsA may also provide information about the risk for developing uveitis. For example, dactylitis has been linked to a higher risk of developing uveitis in some, but not all, cohorts of patients with PsA, and the risk of uveitis in PsA has been found in many studies to correlate with longer duration of disease.^6-8

The presence of uveitis signals a disruption in the blood-retina barrier and the subsequent entrance of inflammatory cells into the eye. An entire explanation of pathogenesis is beyond the scope of this article; however, it is worth noting that many of the inflammatory mediators of active uveitis mirror those of PsA. For instance, both the mesenchymal cells in enthesitis and the cells of the ciliary body express receptors for interleukin (IL)-23, suggesting a potential role of the signaling pathways involving this cytokine in both diseases.⁹ Another study found increased serum levels of IL-17, a known mediator of PsA disease, in patients with active uveitis.¹⁰ Despite these common pathogenesis links, there are limited data on the utility of certain existing PsA treatments on uveitis manifestations.

Our approach is always to manage uveitis associated with PsA in collaboration with a specialized and experienced ophthalmologist. Uncontrolled uveitis can be vision threatening and contribute to long-term morbidity associated with PsA, so timely recognition, evaluation, and appropriate treatment are important. Ocular glucocorticoid (GC) drops may be used as first-line therapy, particularly for anterior uveitis, to quickly quell inflammation. Escalation to systemic GCs for more severe or posteriorly localized disease may be considered carefully, given the known risk of worsening skin psoriasis (PsO) with GC withdrawal after a course of therapy. Use of GC-sparing therapy should be determined on a case-by-case basis. While generalized, noninfectious uveitis often resolves with GC treatment, the risk of uveitis recurrence in patients with PsA and the challenges of systemic GCs with PsO lead us to frequently consider GC-sparing therapy that addresses ocular, musculoskeletal, and cutaneous manifestations. Tumor necrosis factor inhibitors (TNF-I) are our typical first-line considerations for GC-sparing therapy in patients with PsA with inflammatory joint symptoms and uveitis, although nonbiologic therapy can be considered first-line therapy in select populations.

Data establishing the efficacy of TNF-I come largely from randomized controlled trials (RCTs) of adalimumab (ADA) compared to placebo in noninfectious uveitis.¹¹ While these trials focused on idiopathic posterior or pan-uveitis, these data have been extrapolated to SpA-associated anterior uveitis, and large registry analyses have supported use of TNF-I in this population.¹² When selecting a particular TNF-I in a patient with current or past uveitis, we frequently start with ADA, based on supportive, albeit uncontrolled, data suggesting a reduction in the risk of recurrence with this agent in patients with SpA and uveitis.¹² For patients who are unable to tolerate subcutaneous injections, who fail ADA, or who we suspect will require higher, titratable dosing, we favor infliximab infusions. Other data suggest that golimumab and certolizumab are also reasonable alternatives.^13,14 We do not generally use etanercept, as the limited data that are available suggest that it is less effective at reducing risk of uveitis recurrence.¹² Methotrexate or leflunomide may be an appropriate first line choice for patients with peripheral-predominant PsA and uveitis, but it is important to note that these agents are not effective for axial disease.

Despite the mechanistic data implicating the role of IL-17 in uveitis associated with PsA, the IL-17A inhibitor, secukinumab, failed to show a reduction in uveitis recurrence, compared to placebo, in pooled analysis of RCTs of noninfectious uveitis.¹⁵ However, a phase 2 trial of intravenous secukinumab in noninfectious uveitis showed promise, possibly because this dosing regimen can achieve higher effective concentrations.¹⁶ It is not our current practice to use secukinumab or ixekizumab as a first-line therapy in patients with PsA and concurrent uveitis, owing to a lack of data supporting efficacy. A novel IL-17A/F inhibitor, bimekizumab (BKZ), has recently been used in several successful phase 3 trials in patients with both TNF-naïve and TNF-nonresponder SpA, including AxSpA and PsA.¹⁷ Interestingly, data from the phase 2 and 3 trials of BKZ found low incidence rates of uveitis in patients with SpA treated with BKZ compared to placebo, suggesting that BKZ might be more effective in uveitis than other IL-17 inhibitors, but these data need to be confirmed.

Successful use of Janus kinase (JAK) inhibitors in noninfectious uveitis, including cases associated with inflammatory arthritis, has been described in case reports as well as in current phase 2 trials.¹⁸ The dual IL-12/IL-23 inhibitor, ustekinumab, also showed initial promise in a small, nonrandomized, uncontrolled phase 1/2 study of the treatment of posterior uveitis, as well as success in few case reports of PsA-associated uveitis.¹⁹ However, a post-hoc analysis of extra-intestinal manifestations, including uveitis and iritis, in patients with inflammatory bowel disease treated with ustekinumab found no benefit in preventing or treating ocular disease compared to placebo.²⁰ Given the paucity of available data, JAK inhibitors and the IL-12/IL-23 inhibitor, ustekinumab, are not part of our typical treatment algorithm for patients with PsA-associated uveitis.

In conclusion, uveitis is a frequent extra-articular comorbidity of PsA, and it may present differently than the typical acute onset, unilateral anterior uveitis seen in SpA. While uveitis may share many different immunologic threads with PsA, the most convincing data support the use of TNF-I as a GC-sparing agent in this setting, particularly ADA, infliximab, golimumab, or certolizumab. Our approach is generally to start with these agents or methotrexate when directed therapy is needed for uveitis in PsA. Further investigation into the use of the IL-17A/F inhibitor BKZ and JAK inhibitors, as well as tyrosine kinase 2 inhibitors, in PsA associated uveitis may yield additional options for our patients.²¹

With the growing number of treatment options for psoriatic arthritis (PsA), therapeutic decision-making has shifted to an increasingly tailored and patient-centered approach. A number of factors contribute to the treatment decision-making process, including age, insurance restrictions, route of administration, side effect profile, comorbidities, and extra-articular manifestations of the disease. In this article, we discuss an extra-articular comorbidity, uveitis, which is frequently seen in patients with PsA. We discuss clinical characteristics of uveitis associated with PsA and describe how the presence of uveitis influences our treatment approach to PsA, based on existing data.

Uveitis refers broadly to inflammation of the uvea, the vascularized and pigmented layer of the eye composed of the iris, the ciliary body, and the choroid. While infection is a common cause of uveitis, many cases are noninfectious and are often associated with an underlying autoimmune or systemic inflammatory disorder. Uveitis is frequently reported in diseases in the spondyloarthritis (SpA) family, including axial spondyloarthritis (AxSpA) and reactive arthritis, as well as PsA. Exact estimates of the prevalence of uveitis in PsA vary widely from 7%-25%, depending on the particular cohort studied.^1,2 In all forms of SpA, the anterior chamber of the uvea is the most likely to be affected.³ However, compared to patients with AxSpA, patients with PsA appear to have a higher rate of posterior involvement. In addition, patients with PsA appear to have higher frequencies of insidious, bilateral uveitis, as compared to the acute, unilateral, anterior uveitis that is most characteristic of AxSpA.⁴ Women with PsA may be more likely than men to experience uveitis, although this has not been a consistent finding.⁵ 

Patients with PsA who are human leukocyte antigen B27 (HLA-B27) positive may be at risk for more severe and refractory anterior uveitis compared to those who do not express the allele.⁵ Those who are HLA-B27 positive are also known to have higher rates of axial involvement. It has therefore been postulated that 2 phenotypes of uveitis may exist in PsA: patients who are HLA-B27 positive who have axial disease and severe, unilateral anterior uveitis reminiscent of other forms of SpA, and patients who are HLA-B27 negative, often women, with peripheral-predominant arthritis who are prone to the classic anterior uveitis but may also develop atypical bilateral, insidious, and/or posterior involvement.⁴ Specific characteristics of PsA may also provide information about the risk for developing uveitis. For example, dactylitis has been linked to a higher risk of developing uveitis in some, but not all, cohorts of patients with PsA, and the risk of uveitis in PsA has been found in many studies to correlate with longer duration of disease.^6-8

The presence of uveitis signals a disruption in the blood-retina barrier and the subsequent entrance of inflammatory cells into the eye. An entire explanation of pathogenesis is beyond the scope of this article; however, it is worth noting that many of the inflammatory mediators of active uveitis mirror those of PsA. For instance, both the mesenchymal cells in enthesitis and the cells of the ciliary body express receptors for interleukin (IL)-23, suggesting a potential role of the signaling pathways involving this cytokine in both diseases.⁹ Another study found increased serum levels of IL-17, a known mediator of PsA disease, in patients with active uveitis.¹⁰ Despite these common pathogenesis links, there are limited data on the utility of certain existing PsA treatments on uveitis manifestations.

Our approach is always to manage uveitis associated with PsA in collaboration with a specialized and experienced ophthalmologist. Uncontrolled uveitis can be vision threatening and contribute to long-term morbidity associated with PsA, so timely recognition, evaluation, and appropriate treatment are important. Ocular glucocorticoid (GC) drops may be used as first-line therapy, particularly for anterior uveitis, to quickly quell inflammation. Escalation to systemic GCs for more severe or posteriorly localized disease may be considered carefully, given the known risk of worsening skin psoriasis (PsO) with GC withdrawal after a course of therapy. Use of GC-sparing therapy should be determined on a case-by-case basis. While generalized, noninfectious uveitis often resolves with GC treatment, the risk of uveitis recurrence in patients with PsA and the challenges of systemic GCs with PsO lead us to frequently consider GC-sparing therapy that addresses ocular, musculoskeletal, and cutaneous manifestations. Tumor necrosis factor inhibitors (TNF-I) are our typical first-line considerations for GC-sparing therapy in patients with PsA with inflammatory joint symptoms and uveitis, although nonbiologic therapy can be considered first-line therapy in select populations.

Data establishing the efficacy of TNF-I come largely from randomized controlled trials (RCTs) of adalimumab (ADA) compared to placebo in noninfectious uveitis.¹¹ While these trials focused on idiopathic posterior or pan-uveitis, these data have been extrapolated to SpA-associated anterior uveitis, and large registry analyses have supported use of TNF-I in this population.¹² When selecting a particular TNF-I in a patient with current or past uveitis, we frequently start with ADA, based on supportive, albeit uncontrolled, data suggesting a reduction in the risk of recurrence with this agent in patients with SpA and uveitis.¹² For patients who are unable to tolerate subcutaneous injections, who fail ADA, or who we suspect will require higher, titratable dosing, we favor infliximab infusions. Other data suggest that golimumab and certolizumab are also reasonable alternatives.^13,14 We do not generally use etanercept, as the limited data that are available suggest that it is less effective at reducing risk of uveitis recurrence.¹² Methotrexate or leflunomide may be an appropriate first line choice for patients with peripheral-predominant PsA and uveitis, but it is important to note that these agents are not effective for axial disease.

Despite the mechanistic data implicating the role of IL-17 in uveitis associated with PsA, the IL-17A inhibitor, secukinumab, failed to show a reduction in uveitis recurrence, compared to placebo, in pooled analysis of RCTs of noninfectious uveitis.¹⁵ However, a phase 2 trial of intravenous secukinumab in noninfectious uveitis showed promise, possibly because this dosing regimen can achieve higher effective concentrations.¹⁶ It is not our current practice to use secukinumab or ixekizumab as a first-line therapy in patients with PsA and concurrent uveitis, owing to a lack of data supporting efficacy. A novel IL-17A/F inhibitor, bimekizumab (BKZ), has recently been used in several successful phase 3 trials in patients with both TNF-naïve and TNF-nonresponder SpA, including AxSpA and PsA.¹⁷ Interestingly, data from the phase 2 and 3 trials of BKZ found low incidence rates of uveitis in patients with SpA treated with BKZ compared to placebo, suggesting that BKZ might be more effective in uveitis than other IL-17 inhibitors, but these data need to be confirmed.

Successful use of Janus kinase (JAK) inhibitors in noninfectious uveitis, including cases associated with inflammatory arthritis, has been described in case reports as well as in current phase 2 trials.¹⁸ The dual IL-12/IL-23 inhibitor, ustekinumab, also showed initial promise in a small, nonrandomized, uncontrolled phase 1/2 study of the treatment of posterior uveitis, as well as success in few case reports of PsA-associated uveitis.¹⁹ However, a post-hoc analysis of extra-intestinal manifestations, including uveitis and iritis, in patients with inflammatory bowel disease treated with ustekinumab found no benefit in preventing or treating ocular disease compared to placebo.²⁰ Given the paucity of available data, JAK inhibitors and the IL-12/IL-23 inhibitor, ustekinumab, are not part of our typical treatment algorithm for patients with PsA-associated uveitis.

In conclusion, uveitis is a frequent extra-articular comorbidity of PsA, and it may present differently than the typical acute onset, unilateral anterior uveitis seen in SpA. While uveitis may share many different immunologic threads with PsA, the most convincing data support the use of TNF-I as a GC-sparing agent in this setting, particularly ADA, infliximab, golimumab, or certolizumab. Our approach is generally to start with these agents or methotrexate when directed therapy is needed for uveitis in PsA. Further investigation into the use of the IL-17A/F inhibitor BKZ and JAK inhibitors, as well as tyrosine kinase 2 inhibitors, in PsA associated uveitis may yield additional options for our patients.²¹

With the growing number of treatment options for psoriatic arthritis (PsA), therapeutic decision-making has shifted to an increasingly tailored and patient-centered approach. A number of factors contribute to the treatment decision-making process, including age, insurance restrictions, route of administration, side effect profile, comorbidities, and extra-articular manifestations of the disease. In this article, we discuss an extra-articular comorbidity, uveitis, which is frequently seen in patients with PsA. We discuss clinical characteristics of uveitis associated with PsA and describe how the presence of uveitis influences our treatment approach to PsA, based on existing data.

Uveitis refers broadly to inflammation of the uvea, the vascularized and pigmented layer of the eye composed of the iris, the ciliary body, and the choroid. While infection is a common cause of uveitis, many cases are noninfectious and are often associated with an underlying autoimmune or systemic inflammatory disorder. Uveitis is frequently reported in diseases in the spondyloarthritis (SpA) family, including axial spondyloarthritis (AxSpA) and reactive arthritis, as well as PsA. Exact estimates of the prevalence of uveitis in PsA vary widely from 7%-25%, depending on the particular cohort studied.^1,2 In all forms of SpA, the anterior chamber of the uvea is the most likely to be affected.³ However, compared to patients with AxSpA, patients with PsA appear to have a higher rate of posterior involvement. In addition, patients with PsA appear to have higher frequencies of insidious, bilateral uveitis, as compared to the acute, unilateral, anterior uveitis that is most characteristic of AxSpA.⁴ Women with PsA may be more likely than men to experience uveitis, although this has not been a consistent finding.⁵ 

Patients with PsA who are human leukocyte antigen B27 (HLA-B27) positive may be at risk for more severe and refractory anterior uveitis compared to those who do not express the allele.⁵ Those who are HLA-B27 positive are also known to have higher rates of axial involvement. It has therefore been postulated that 2 phenotypes of uveitis may exist in PsA: patients who are HLA-B27 positive who have axial disease and severe, unilateral anterior uveitis reminiscent of other forms of SpA, and patients who are HLA-B27 negative, often women, with peripheral-predominant arthritis who are prone to the classic anterior uveitis but may also develop atypical bilateral, insidious, and/or posterior involvement.⁴ Specific characteristics of PsA may also provide information about the risk for developing uveitis. For example, dactylitis has been linked to a higher risk of developing uveitis in some, but not all, cohorts of patients with PsA, and the risk of uveitis in PsA has been found in many studies to correlate with longer duration of disease.^6-8

The presence of uveitis signals a disruption in the blood-retina barrier and the subsequent entrance of inflammatory cells into the eye. An entire explanation of pathogenesis is beyond the scope of this article; however, it is worth noting that many of the inflammatory mediators of active uveitis mirror those of PsA. For instance, both the mesenchymal cells in enthesitis and the cells of the ciliary body express receptors for interleukin (IL)-23, suggesting a potential role of the signaling pathways involving this cytokine in both diseases.⁹ Another study found increased serum levels of IL-17, a known mediator of PsA disease, in patients with active uveitis.¹⁰ Despite these common pathogenesis links, there are limited data on the utility of certain existing PsA treatments on uveitis manifestations.

Our approach is always to manage uveitis associated with PsA in collaboration with a specialized and experienced ophthalmologist. Uncontrolled uveitis can be vision threatening and contribute to long-term morbidity associated with PsA, so timely recognition, evaluation, and appropriate treatment are important. Ocular glucocorticoid (GC) drops may be used as first-line therapy, particularly for anterior uveitis, to quickly quell inflammation. Escalation to systemic GCs for more severe or posteriorly localized disease may be considered carefully, given the known risk of worsening skin psoriasis (PsO) with GC withdrawal after a course of therapy. Use of GC-sparing therapy should be determined on a case-by-case basis. While generalized, noninfectious uveitis often resolves with GC treatment, the risk of uveitis recurrence in patients with PsA and the challenges of systemic GCs with PsO lead us to frequently consider GC-sparing therapy that addresses ocular, musculoskeletal, and cutaneous manifestations. Tumor necrosis factor inhibitors (TNF-I) are our typical first-line considerations for GC-sparing therapy in patients with PsA with inflammatory joint symptoms and uveitis, although nonbiologic therapy can be considered first-line therapy in select populations.

Data establishing the efficacy of TNF-I come largely from randomized controlled trials (RCTs) of adalimumab (ADA) compared to placebo in noninfectious uveitis.¹¹ While these trials focused on idiopathic posterior or pan-uveitis, these data have been extrapolated to SpA-associated anterior uveitis, and large registry analyses have supported use of TNF-I in this population.¹² When selecting a particular TNF-I in a patient with current or past uveitis, we frequently start with ADA, based on supportive, albeit uncontrolled, data suggesting a reduction in the risk of recurrence with this agent in patients with SpA and uveitis.¹² For patients who are unable to tolerate subcutaneous injections, who fail ADA, or who we suspect will require higher, titratable dosing, we favor infliximab infusions. Other data suggest that golimumab and certolizumab are also reasonable alternatives.^13,14 We do not generally use etanercept, as the limited data that are available suggest that it is less effective at reducing risk of uveitis recurrence.¹² Methotrexate or leflunomide may be an appropriate first line choice for patients with peripheral-predominant PsA and uveitis, but it is important to note that these agents are not effective for axial disease.

Despite the mechanistic data implicating the role of IL-17 in uveitis associated with PsA, the IL-17A inhibitor, secukinumab, failed to show a reduction in uveitis recurrence, compared to placebo, in pooled analysis of RCTs of noninfectious uveitis.¹⁵ However, a phase 2 trial of intravenous secukinumab in noninfectious uveitis showed promise, possibly because this dosing regimen can achieve higher effective concentrations.¹⁶ It is not our current practice to use secukinumab or ixekizumab as a first-line therapy in patients with PsA and concurrent uveitis, owing to a lack of data supporting efficacy. A novel IL-17A/F inhibitor, bimekizumab (BKZ), has recently been used in several successful phase 3 trials in patients with both TNF-naïve and TNF-nonresponder SpA, including AxSpA and PsA.¹⁷ Interestingly, data from the phase 2 and 3 trials of BKZ found low incidence rates of uveitis in patients with SpA treated with BKZ compared to placebo, suggesting that BKZ might be more effective in uveitis than other IL-17 inhibitors, but these data need to be confirmed.

Successful use of Janus kinase (JAK) inhibitors in noninfectious uveitis, including cases associated with inflammatory arthritis, has been described in case reports as well as in current phase 2 trials.¹⁸ The dual IL-12/IL-23 inhibitor, ustekinumab, also showed initial promise in a small, nonrandomized, uncontrolled phase 1/2 study of the treatment of posterior uveitis, as well as success in few case reports of PsA-associated uveitis.¹⁹ However, a post-hoc analysis of extra-intestinal manifestations, including uveitis and iritis, in patients with inflammatory bowel disease treated with ustekinumab found no benefit in preventing or treating ocular disease compared to placebo.²⁰ Given the paucity of available data, JAK inhibitors and the IL-12/IL-23 inhibitor, ustekinumab, are not part of our typical treatment algorithm for patients with PsA-associated uveitis.

In conclusion, uveitis is a frequent extra-articular comorbidity of PsA, and it may present differently than the typical acute onset, unilateral anterior uveitis seen in SpA. While uveitis may share many different immunologic threads with PsA, the most convincing data support the use of TNF-I as a GC-sparing agent in this setting, particularly ADA, infliximab, golimumab, or certolizumab. Our approach is generally to start with these agents or methotrexate when directed therapy is needed for uveitis in PsA. Further investigation into the use of the IL-17A/F inhibitor BKZ and JAK inhibitors, as well as tyrosine kinase 2 inhibitors, in PsA associated uveitis may yield additional options for our patients.²¹