MDedge Dermatology

To the Editor:

Raynaud phenomenon (RP) is an episodic vasospasm of the digits that can lead to ulceration, gangrene, and autoamputation with prolonged ischemia. OnabotulinumtoxinA has been implemented as a treatment of intractable RP by paralyzing the muscles of the digital arteries. We report a case of a woman with severe RP secondary to systemic lupus erythematosus (SLE) who was treated with onabotulinumtoxinA injections after multiple treatment modalities failed to improve her condition. We describe the dosage and injection technique used to produce clinical improvement in our patient and compare it to prior reports in the literature.

A 33-year-old woman presented to the emergency department for worsening foot pain of 5 days' duration with dusky purple color changes concerning for impending Raynaud crisis related to RP. The patient had a history of antiphospholipid antibody syndrome (APS) and SLE with overlapping symptoms of polymyositis and scleroderma. She had been hospitalized for RP multiple times prior to the current admission. She was medically managed with nifedipine, sildenafil, losartan potassium, aspirin, alprostadil, and prostaglandin infusions, and was surgically managed with a right-hand sympathectomy and right ulnar artery bypass graft that had subsequently thrombosed. At the current presentation, she had painful dusky toes on both feet though more pronounced on the left foot. She endorsed foot pain while walking and tenderness to palpation of the fingers, which were minimally improved with intravenous prostaglandins.

Physical examination revealed blanching of the digits in both hands with pits in the right fourth and left first digits. Dusky patches overlaid all the toes as well as the superior plantar aspects of the feet (Figure 1). Given the history of APS, a punch biopsy was performed on the left medial plantar foot and results showed no histologic evidence of vasculitis or vasculopathy. Necrotic foci were present on the left and right second metatarsal bones, which were not reperfusable (Figure 2). The clinical findings and punch biopsy results favored RP as opposed to vasculopathy from APS.

Several interventions were attempted, and after 4 days with no response, the patient agreed to receive treatment with onabotulinumtoxinA. OnabotulinumtoxinA (5 U) was injected into the subcutaneous tissue of the medial and lateral aspects of each of the first and second toes near the proximal phalanges (40 U total). However, treatment could not be completed due to severe pain caused by the injections despite preprocedure regional nerve blocks to both lower extremities, preinjection icing, and lorazepam. Two days later, the patient tolerated onabotulinumtoxinA injections of all remaining digits of both feet (60 U total). She noted slight clinical improvement soon thereafter. One week after treatment of all 10 toes, she reported decreased pain and reduced duskiness of both feet (Figure 3).

One month later, the patient endorsed recurring pain in the hands and feet. Physical examination revealed reticular cyanosis and increased violaceous patches of the hands; the feet were overall unchanged from the prior hospitalization. At 4-month follow-up, there was gangrene on the left second, third, and fifth toe in addition to areas of induration noted on the fingers. She was repeatedly hospitalized over the next 6 months for pain management and gangrene of the toes, and finally underwent an amputation of the left and right second toe at the proximal and middle phalanx, respectively. She currently is continuing extensive medical management for pain and gangrene of the digits; she has not received additional onabotulinumtoxinA injections.

Raynaud phenomenon is a vascular disorder characterized by intermittent arteriolar vasospasm of the digits, often due to cold temperature or stress. Approximately 90% of RP cases are primarily idiopathic, with the remaining cases secondary to other diseases, typically systemic sclerosis, SLE, or mixed connective tissue disease.¹ Symptoms present with characteristic changing of hands from white (ischemia) to blue (hypoxia) to red (reperfusion). Episodic attacks of vasospasm and ischemia can be painful and lead to digital ulcerations and necrosis of the digits or hands. Other complications including digital tuft pits, pterygium inversum unguis, or torturous nail fold capillaries with capillary dropout also may be seen.²

Although the etiology is multifactorial, the pathophysiology primarily is due to an imbalance of vasodilation and vasoconstriction. Perturbed levels of vasodilatory mediators include nitric oxide, prostacyclin, and calcitonin gene-related peptide.³ Meanwhile, abnormal neural sympathetic control of α-adrenergic receptors located on smooth muscle vasculature and subsequent endothelial hyperproliferation may contribute to inappropriate vasoconstriction.⁴

The first-line therapy for mild to moderate disease refractory to conservative management includes monotherapy with dihydropyridine calcium channel blockers. For severe disease, combination therapy involves addition of other classes of medications including phosphodiesterase 5 inhibitors, topical nitrates, angiotensin receptor blockers, or selective serotonin reuptake inhibitors. Intravenous prostacyclin, endothelin receptor blockers, and onabotulinumtoxinA injections may be added as third-line therapy. Finally, surgical management including sympathectomy with continued pharmacologic therapy may be needed for disease recalcitrant to the aforementioned options.²

OnabotulinumtoxinA is a neurotoxin produced by the bacterium Clostridium botulinum. The toxin’s mechanism of action involves inhibition of the release of presynaptic acetylcholine-containing vesicles at the neuromuscular junction through cleavage of sensory nerve action potential receptor proteins. In addition, it inhibits smooth muscle vasoconstriction and pain by blocking α₂-adrenergic receptors on blood vessels and chronic pain-transmitting C fibers in nerves, respectively.^3,5

Only recently has onabotulinumtoxinA been used for treatment of RP. Botulinum toxin is approved for the treatment of spastic and dystonic diseases such as blepharospasm, headaches in patients with chronic migraines, upper limb spasticity, cervical dystonia, torticollis, ocular strabismus, and hyperhidrosis.³ However, the versatility of its therapeutic effects is evident in its broad off-label clinical applications, including achalasia; carpal tunnel syndrome; and spasticity relating to stroke, paraplegia, and cerebral palsy, among many others.⁵

Few studies have analyzed the use of onabotulinumtoxinA for the treatment of RP.^3,6 There is no consensus yet regarding dose, dilution, or injection sites. One vial of onabotulinumtoxinA contains 100 U and is reconstituted in 20 mL of normal saline to produce 5 U/mL. The simplest technique involves the injection of 5 U into the medial and lateral aspects of each finger at its base, at the level of or just proximal to the A1 pulley, for a total of 50 U per hand.⁷ In the foot, injection can be made at the base of each toe near the proximal phalanges. A regimen of 50 to 100 U per hand was used by Neumeister et al⁵ on 19 patients, who subsequently standardized it to 10 U on each neurovascular bundle in a follow-up study,⁷ giving a total volume of 2 mL per injection. Associated pain or a burning sensation initially may be experienced, which may be mitigated by a lidocaine hydrochloride wrist block prior to injection.⁷ This technique produced immediate and lasting pain relief, increased tissue perfusion, and resolved digital ulcers in 28 of 33 patients. Most patients reported immediate relief, and a few noted gradual reduction in pain and resolution of chronic ulcers within 2 months. Of the 33 patients, 7 (21.2%) required repeat injections for recurrent pain, but the majority were pain free up to 6 years later with a single injection schedule.⁷

Injection into the palmar region, wrists, and/or fingers also may be performed. Effects of using different injection sites (eg, neurovascular bundle, distal palm, proximal hand) have been explored and were not notably different between these locations.⁸ Lastly, the frequency of injections may be attenuated according to the spectrum and severity of the patient’s symptoms. In a report of 11 patients who received a total of 100 U of onabotulinumtoxinA per hand, 5 required repeat injections within 3 to 8 months.⁹

Studies have reported onabotulinumtoxinA to be a promising option for the treatment of intractable symptoms. Likewise, our patient had a notable reduction in pain with signs of clinical improvement within 24 to 48 hours after injection. The need for amputation 6 months later likely was because the patient’s toes were already necrosing prior to treatment with onabotulinumtoxinA. Thus, the timing of intervention may play a critical role in response to onabotulinumtoxinA injections, particularly because the severity of our patient’s presentation was comparable to other cases reported in the literature. Even in reports using a smaller dose—2 U injected into each toe as opposed to 10 U per toe, as in our case—follow-up showed favorable results.¹⁰ In other reports, response can be perceived within days to a week, with remarkable improvement of numbness, pain, digit color, and wound resolution, in addition to decreased frequency and severity of attacks. Moreover, greater vasodilation and subsequent tissue perfusion have been evidenced by objective measures including digital transcutaneous oxygen saturation and Doppler sonography.^7,8 Side effects, which are minimal and temporary, include local pain triggering a vasospastic attack and intrinsic muscle weakness; more rarely, dysesthesia and thenar eminence atrophy have been reported.¹¹

Available studies have shown onabotulinumtoxinA to produce favorable results in the treatment of vasospastic disease. We suspect that an earlier intervention for our patient—before necrosis of the toes developed—would have led to a more positive outcome, consistent with other reports. Treatment with onabotulinumtoxinA is an approach to consider when the standard-of-care treatments for RP have been exhausted, as timely intervention may prevent the need for surgery. The indications and appropriate dosing protocol remain to be defined, in addition to more thorough evaluation of its efficacy relative to other medical and surgical options.

To the Editor:

Raynaud phenomenon (RP) is an episodic vasospasm of the digits that can lead to ulceration, gangrene, and autoamputation with prolonged ischemia. OnabotulinumtoxinA has been implemented as a treatment of intractable RP by paralyzing the muscles of the digital arteries. We report a case of a woman with severe RP secondary to systemic lupus erythematosus (SLE) who was treated with onabotulinumtoxinA injections after multiple treatment modalities failed to improve her condition. We describe the dosage and injection technique used to produce clinical improvement in our patient and compare it to prior reports in the literature.

A 33-year-old woman presented to the emergency department for worsening foot pain of 5 days' duration with dusky purple color changes concerning for impending Raynaud crisis related to RP. The patient had a history of antiphospholipid antibody syndrome (APS) and SLE with overlapping symptoms of polymyositis and scleroderma. She had been hospitalized for RP multiple times prior to the current admission. She was medically managed with nifedipine, sildenafil, losartan potassium, aspirin, alprostadil, and prostaglandin infusions, and was surgically managed with a right-hand sympathectomy and right ulnar artery bypass graft that had subsequently thrombosed. At the current presentation, she had painful dusky toes on both feet though more pronounced on the left foot. She endorsed foot pain while walking and tenderness to palpation of the fingers, which were minimally improved with intravenous prostaglandins.

Physical examination revealed blanching of the digits in both hands with pits in the right fourth and left first digits. Dusky patches overlaid all the toes as well as the superior plantar aspects of the feet (Figure 1). Given the history of APS, a punch biopsy was performed on the left medial plantar foot and results showed no histologic evidence of vasculitis or vasculopathy. Necrotic foci were present on the left and right second metatarsal bones, which were not reperfusable (Figure 2). The clinical findings and punch biopsy results favored RP as opposed to vasculopathy from APS.

Several interventions were attempted, and after 4 days with no response, the patient agreed to receive treatment with onabotulinumtoxinA. OnabotulinumtoxinA (5 U) was injected into the subcutaneous tissue of the medial and lateral aspects of each of the first and second toes near the proximal phalanges (40 U total). However, treatment could not be completed due to severe pain caused by the injections despite preprocedure regional nerve blocks to both lower extremities, preinjection icing, and lorazepam. Two days later, the patient tolerated onabotulinumtoxinA injections of all remaining digits of both feet (60 U total). She noted slight clinical improvement soon thereafter. One week after treatment of all 10 toes, she reported decreased pain and reduced duskiness of both feet (Figure 3).

One month later, the patient endorsed recurring pain in the hands and feet. Physical examination revealed reticular cyanosis and increased violaceous patches of the hands; the feet were overall unchanged from the prior hospitalization. At 4-month follow-up, there was gangrene on the left second, third, and fifth toe in addition to areas of induration noted on the fingers. She was repeatedly hospitalized over the next 6 months for pain management and gangrene of the toes, and finally underwent an amputation of the left and right second toe at the proximal and middle phalanx, respectively. She currently is continuing extensive medical management for pain and gangrene of the digits; she has not received additional onabotulinumtoxinA injections.

Raynaud phenomenon is a vascular disorder characterized by intermittent arteriolar vasospasm of the digits, often due to cold temperature or stress. Approximately 90% of RP cases are primarily idiopathic, with the remaining cases secondary to other diseases, typically systemic sclerosis, SLE, or mixed connective tissue disease.¹ Symptoms present with characteristic changing of hands from white (ischemia) to blue (hypoxia) to red (reperfusion). Episodic attacks of vasospasm and ischemia can be painful and lead to digital ulcerations and necrosis of the digits or hands. Other complications including digital tuft pits, pterygium inversum unguis, or torturous nail fold capillaries with capillary dropout also may be seen.²

Although the etiology is multifactorial, the pathophysiology primarily is due to an imbalance of vasodilation and vasoconstriction. Perturbed levels of vasodilatory mediators include nitric oxide, prostacyclin, and calcitonin gene-related peptide.³ Meanwhile, abnormal neural sympathetic control of α-adrenergic receptors located on smooth muscle vasculature and subsequent endothelial hyperproliferation may contribute to inappropriate vasoconstriction.⁴

The first-line therapy for mild to moderate disease refractory to conservative management includes monotherapy with dihydropyridine calcium channel blockers. For severe disease, combination therapy involves addition of other classes of medications including phosphodiesterase 5 inhibitors, topical nitrates, angiotensin receptor blockers, or selective serotonin reuptake inhibitors. Intravenous prostacyclin, endothelin receptor blockers, and onabotulinumtoxinA injections may be added as third-line therapy. Finally, surgical management including sympathectomy with continued pharmacologic therapy may be needed for disease recalcitrant to the aforementioned options.²

OnabotulinumtoxinA is a neurotoxin produced by the bacterium Clostridium botulinum. The toxin’s mechanism of action involves inhibition of the release of presynaptic acetylcholine-containing vesicles at the neuromuscular junction through cleavage of sensory nerve action potential receptor proteins. In addition, it inhibits smooth muscle vasoconstriction and pain by blocking α₂-adrenergic receptors on blood vessels and chronic pain-transmitting C fibers in nerves, respectively.^3,5

Only recently has onabotulinumtoxinA been used for treatment of RP. Botulinum toxin is approved for the treatment of spastic and dystonic diseases such as blepharospasm, headaches in patients with chronic migraines, upper limb spasticity, cervical dystonia, torticollis, ocular strabismus, and hyperhidrosis.³ However, the versatility of its therapeutic effects is evident in its broad off-label clinical applications, including achalasia; carpal tunnel syndrome; and spasticity relating to stroke, paraplegia, and cerebral palsy, among many others.⁵

Few studies have analyzed the use of onabotulinumtoxinA for the treatment of RP.^3,6 There is no consensus yet regarding dose, dilution, or injection sites. One vial of onabotulinumtoxinA contains 100 U and is reconstituted in 20 mL of normal saline to produce 5 U/mL. The simplest technique involves the injection of 5 U into the medial and lateral aspects of each finger at its base, at the level of or just proximal to the A1 pulley, for a total of 50 U per hand.⁷ In the foot, injection can be made at the base of each toe near the proximal phalanges. A regimen of 50 to 100 U per hand was used by Neumeister et al⁵ on 19 patients, who subsequently standardized it to 10 U on each neurovascular bundle in a follow-up study,⁷ giving a total volume of 2 mL per injection. Associated pain or a burning sensation initially may be experienced, which may be mitigated by a lidocaine hydrochloride wrist block prior to injection.⁷ This technique produced immediate and lasting pain relief, increased tissue perfusion, and resolved digital ulcers in 28 of 33 patients. Most patients reported immediate relief, and a few noted gradual reduction in pain and resolution of chronic ulcers within 2 months. Of the 33 patients, 7 (21.2%) required repeat injections for recurrent pain, but the majority were pain free up to 6 years later with a single injection schedule.⁷

Injection into the palmar region, wrists, and/or fingers also may be performed. Effects of using different injection sites (eg, neurovascular bundle, distal palm, proximal hand) have been explored and were not notably different between these locations.⁸ Lastly, the frequency of injections may be attenuated according to the spectrum and severity of the patient’s symptoms. In a report of 11 patients who received a total of 100 U of onabotulinumtoxinA per hand, 5 required repeat injections within 3 to 8 months.⁹

Studies have reported onabotulinumtoxinA to be a promising option for the treatment of intractable symptoms. Likewise, our patient had a notable reduction in pain with signs of clinical improvement within 24 to 48 hours after injection. The need for amputation 6 months later likely was because the patient’s toes were already necrosing prior to treatment with onabotulinumtoxinA. Thus, the timing of intervention may play a critical role in response to onabotulinumtoxinA injections, particularly because the severity of our patient’s presentation was comparable to other cases reported in the literature. Even in reports using a smaller dose—2 U injected into each toe as opposed to 10 U per toe, as in our case—follow-up showed favorable results.¹⁰ In other reports, response can be perceived within days to a week, with remarkable improvement of numbness, pain, digit color, and wound resolution, in addition to decreased frequency and severity of attacks. Moreover, greater vasodilation and subsequent tissue perfusion have been evidenced by objective measures including digital transcutaneous oxygen saturation and Doppler sonography.^7,8 Side effects, which are minimal and temporary, include local pain triggering a vasospastic attack and intrinsic muscle weakness; more rarely, dysesthesia and thenar eminence atrophy have been reported.¹¹

Available studies have shown onabotulinumtoxinA to produce favorable results in the treatment of vasospastic disease. We suspect that an earlier intervention for our patient—before necrosis of the toes developed—would have led to a more positive outcome, consistent with other reports. Treatment with onabotulinumtoxinA is an approach to consider when the standard-of-care treatments for RP have been exhausted, as timely intervention may prevent the need for surgery. The indications and appropriate dosing protocol remain to be defined, in addition to more thorough evaluation of its efficacy relative to other medical and surgical options.

To the Editor:

Raynaud phenomenon (RP) is an episodic vasospasm of the digits that can lead to ulceration, gangrene, and autoamputation with prolonged ischemia. OnabotulinumtoxinA has been implemented as a treatment of intractable RP by paralyzing the muscles of the digital arteries. We report a case of a woman with severe RP secondary to systemic lupus erythematosus (SLE) who was treated with onabotulinumtoxinA injections after multiple treatment modalities failed to improve her condition. We describe the dosage and injection technique used to produce clinical improvement in our patient and compare it to prior reports in the literature.

A 33-year-old woman presented to the emergency department for worsening foot pain of 5 days' duration with dusky purple color changes concerning for impending Raynaud crisis related to RP. The patient had a history of antiphospholipid antibody syndrome (APS) and SLE with overlapping symptoms of polymyositis and scleroderma. She had been hospitalized for RP multiple times prior to the current admission. She was medically managed with nifedipine, sildenafil, losartan potassium, aspirin, alprostadil, and prostaglandin infusions, and was surgically managed with a right-hand sympathectomy and right ulnar artery bypass graft that had subsequently thrombosed. At the current presentation, she had painful dusky toes on both feet though more pronounced on the left foot. She endorsed foot pain while walking and tenderness to palpation of the fingers, which were minimally improved with intravenous prostaglandins.

Physical examination revealed blanching of the digits in both hands with pits in the right fourth and left first digits. Dusky patches overlaid all the toes as well as the superior plantar aspects of the feet (Figure 1). Given the history of APS, a punch biopsy was performed on the left medial plantar foot and results showed no histologic evidence of vasculitis or vasculopathy. Necrotic foci were present on the left and right second metatarsal bones, which were not reperfusable (Figure 2). The clinical findings and punch biopsy results favored RP as opposed to vasculopathy from APS.

Several interventions were attempted, and after 4 days with no response, the patient agreed to receive treatment with onabotulinumtoxinA. OnabotulinumtoxinA (5 U) was injected into the subcutaneous tissue of the medial and lateral aspects of each of the first and second toes near the proximal phalanges (40 U total). However, treatment could not be completed due to severe pain caused by the injections despite preprocedure regional nerve blocks to both lower extremities, preinjection icing, and lorazepam. Two days later, the patient tolerated onabotulinumtoxinA injections of all remaining digits of both feet (60 U total). She noted slight clinical improvement soon thereafter. One week after treatment of all 10 toes, she reported decreased pain and reduced duskiness of both feet (Figure 3).

One month later, the patient endorsed recurring pain in the hands and feet. Physical examination revealed reticular cyanosis and increased violaceous patches of the hands; the feet were overall unchanged from the prior hospitalization. At 4-month follow-up, there was gangrene on the left second, third, and fifth toe in addition to areas of induration noted on the fingers. She was repeatedly hospitalized over the next 6 months for pain management and gangrene of the toes, and finally underwent an amputation of the left and right second toe at the proximal and middle phalanx, respectively. She currently is continuing extensive medical management for pain and gangrene of the digits; she has not received additional onabotulinumtoxinA injections.

Raynaud phenomenon is a vascular disorder characterized by intermittent arteriolar vasospasm of the digits, often due to cold temperature or stress. Approximately 90% of RP cases are primarily idiopathic, with the remaining cases secondary to other diseases, typically systemic sclerosis, SLE, or mixed connective tissue disease.¹ Symptoms present with characteristic changing of hands from white (ischemia) to blue (hypoxia) to red (reperfusion). Episodic attacks of vasospasm and ischemia can be painful and lead to digital ulcerations and necrosis of the digits or hands. Other complications including digital tuft pits, pterygium inversum unguis, or torturous nail fold capillaries with capillary dropout also may be seen.²

Although the etiology is multifactorial, the pathophysiology primarily is due to an imbalance of vasodilation and vasoconstriction. Perturbed levels of vasodilatory mediators include nitric oxide, prostacyclin, and calcitonin gene-related peptide.³ Meanwhile, abnormal neural sympathetic control of α-adrenergic receptors located on smooth muscle vasculature and subsequent endothelial hyperproliferation may contribute to inappropriate vasoconstriction.⁴

The first-line therapy for mild to moderate disease refractory to conservative management includes monotherapy with dihydropyridine calcium channel blockers. For severe disease, combination therapy involves addition of other classes of medications including phosphodiesterase 5 inhibitors, topical nitrates, angiotensin receptor blockers, or selective serotonin reuptake inhibitors. Intravenous prostacyclin, endothelin receptor blockers, and onabotulinumtoxinA injections may be added as third-line therapy. Finally, surgical management including sympathectomy with continued pharmacologic therapy may be needed for disease recalcitrant to the aforementioned options.²

OnabotulinumtoxinA is a neurotoxin produced by the bacterium Clostridium botulinum. The toxin’s mechanism of action involves inhibition of the release of presynaptic acetylcholine-containing vesicles at the neuromuscular junction through cleavage of sensory nerve action potential receptor proteins. In addition, it inhibits smooth muscle vasoconstriction and pain by blocking α₂-adrenergic receptors on blood vessels and chronic pain-transmitting C fibers in nerves, respectively.^3,5

Only recently has onabotulinumtoxinA been used for treatment of RP. Botulinum toxin is approved for the treatment of spastic and dystonic diseases such as blepharospasm, headaches in patients with chronic migraines, upper limb spasticity, cervical dystonia, torticollis, ocular strabismus, and hyperhidrosis.³ However, the versatility of its therapeutic effects is evident in its broad off-label clinical applications, including achalasia; carpal tunnel syndrome; and spasticity relating to stroke, paraplegia, and cerebral palsy, among many others.⁵

Few studies have analyzed the use of onabotulinumtoxinA for the treatment of RP.^3,6 There is no consensus yet regarding dose, dilution, or injection sites. One vial of onabotulinumtoxinA contains 100 U and is reconstituted in 20 mL of normal saline to produce 5 U/mL. The simplest technique involves the injection of 5 U into the medial and lateral aspects of each finger at its base, at the level of or just proximal to the A1 pulley, for a total of 50 U per hand.⁷ In the foot, injection can be made at the base of each toe near the proximal phalanges. A regimen of 50 to 100 U per hand was used by Neumeister et al⁵ on 19 patients, who subsequently standardized it to 10 U on each neurovascular bundle in a follow-up study,⁷ giving a total volume of 2 mL per injection. Associated pain or a burning sensation initially may be experienced, which may be mitigated by a lidocaine hydrochloride wrist block prior to injection.⁷ This technique produced immediate and lasting pain relief, increased tissue perfusion, and resolved digital ulcers in 28 of 33 patients. Most patients reported immediate relief, and a few noted gradual reduction in pain and resolution of chronic ulcers within 2 months. Of the 33 patients, 7 (21.2%) required repeat injections for recurrent pain, but the majority were pain free up to 6 years later with a single injection schedule.⁷

Injection into the palmar region, wrists, and/or fingers also may be performed. Effects of using different injection sites (eg, neurovascular bundle, distal palm, proximal hand) have been explored and were not notably different between these locations.⁸ Lastly, the frequency of injections may be attenuated according to the spectrum and severity of the patient’s symptoms. In a report of 11 patients who received a total of 100 U of onabotulinumtoxinA per hand, 5 required repeat injections within 3 to 8 months.⁹

Studies have reported onabotulinumtoxinA to be a promising option for the treatment of intractable symptoms. Likewise, our patient had a notable reduction in pain with signs of clinical improvement within 24 to 48 hours after injection. The need for amputation 6 months later likely was because the patient’s toes were already necrosing prior to treatment with onabotulinumtoxinA. Thus, the timing of intervention may play a critical role in response to onabotulinumtoxinA injections, particularly because the severity of our patient’s presentation was comparable to other cases reported in the literature. Even in reports using a smaller dose—2 U injected into each toe as opposed to 10 U per toe, as in our case—follow-up showed favorable results.¹⁰ In other reports, response can be perceived within days to a week, with remarkable improvement of numbness, pain, digit color, and wound resolution, in addition to decreased frequency and severity of attacks. Moreover, greater vasodilation and subsequent tissue perfusion have been evidenced by objective measures including digital transcutaneous oxygen saturation and Doppler sonography.^7,8 Side effects, which are minimal and temporary, include local pain triggering a vasospastic attack and intrinsic muscle weakness; more rarely, dysesthesia and thenar eminence atrophy have been reported.¹¹

Available studies have shown onabotulinumtoxinA to produce favorable results in the treatment of vasospastic disease. We suspect that an earlier intervention for our patient—before necrosis of the toes developed—would have led to a more positive outcome, consistent with other reports. Treatment with onabotulinumtoxinA is an approach to consider when the standard-of-care treatments for RP have been exhausted, as timely intervention may prevent the need for surgery. The indications and appropriate dosing protocol remain to be defined, in addition to more thorough evaluation of its efficacy relative to other medical and surgical options.

A new lawsuit seeking to force the Food and Drug Administration to act on a request to add stricter warnings to finasteride or remove it from the market may rekindle a debate on whether some of the observed side effects from the hair loss drug merit a closer look and, potentially, better counseling and monitoring from clinicians.

The nonprofit advocacy group Public Citizen filed the suit on behalf of the Post-Finasteride Syndrome Foundation (PFSF) in the U.S. District Court for the District of Columbia. The PFSF had filed a citizen’s petition in 2017 that requested that the FDA either take the 1-mg formulation off the market, or add warnings about the potential for erectile dysfunction, depression, and suicidal ideation, among other adverse reactions.

The PFSF has alleged that long-term use of Propecia (and its generic equivalents) can lead to postfinasteride syndrome (PFS), characterized by sexual dysfunction and psycho-neurocognitive symptoms. The symptoms may continue long after men stop taking the drug, according to PFSF.

Public Citizen said the FDA needs to take action in part because U.S. prescriptions of the hair loss formulation “more than doubled from 2015 to 2020,” and online and telemedicine companies such as Hims, Roman, and Keeps “aggressively market and sell generic finasteride for hair loss.” According to GoodRx, a 1-month supply of generic 1-mg tablets costs as little as $8-$10.

Both Canadian and British regulatory authorities have added warnings about depression and suicide to the Propecia label but the FDA has not changed its labeling. An agency spokesperson told this news organization that the “FDA does not comment on the status of pending citizen petitions or on pending litigation.”

Propecia’s developer, Merck, has not responded to several requests for comment from this news organization.

Why some patients develop PFS and others do not is still not understood, but some clinicians said they counsel all patients on the risks of severe and persistent side effects that have been associated with Propecia.

Robert M. Bernstein, MD, of the department of dermatology at Columbia University, New York, and a fellow of the International Society of Hair Restoration Surgery, said that 2%-4% of his patients have some side effects, similar to the original reported incidence, with sexual dysfunction being the most common.

If a man experiences an adverse effect, the drug should be stopped, Dr. Bernstein said in an interview. He noted that “there seems to be a significant increased risk of persistent side effects in people with certain psychiatric conditions, and those people should be counseled carefully before considering the medication.”

“Everybody should be warned that the risk of persistent side effects is real but in the average person it is quite uncommon,” added Dr. Bernstein, founder of Bernstein Medical, a division of Schweiger Dermatology Group focusing on the diagnosis and treatment of hair loss. “I don’t think it should be withdrawn from the market,” he said.

Other countries warn of psychiatric effects

The FDA approved the 1-mg form of finasteride for male pattern hair loss in 1997.

In 2012, the label and the patient insert were updated to state that side effects included less desire for sex, erectile dysfunction, and a decrease in the amount of semen produced, but that those adverse events occurred in less than 2% of men and generally went away in most men who stopped taking the drug.

That label change unleashed a flood of more than 1,000 lawsuits against Merck. The company reportedly settled at least half of them for $4.3 million in 2018. The Superior Court of New Jersey closed out the consolidated class action against Merck in May 2021, noting that all of the cases had been settled or dismissed.

The suits generally accused Merck of not giving adequate warning about sexual side effects, according to an investigation by Reuters. That 2019 special report found that Merck had understated the number of men who experienced sexual side effects and the duration of those symptoms. The news organization also reported that from 2009 to 2018, the FDA received 5,000 reports of sexual or mental health side effects – and sometimes both – in men who took finasteride. Some 350 of the men reported suicidal thoughts, and there were 50 reports of suicide.

Public Citizen’s lawsuit alleges that VigiBase, which is managed by the World Health Organization Collaborating Centre for International Drug Monitoring, lists 378 cases of suicidal ideation, 39 cases of suicide attempt, and 88 cases of completed suicide associated with finasteride use. VigiBase collects data from 153 countries on adverse reactions to medications.

In February 2021, more documents from the class action lawsuits were unsealed in response to a Reuters request. According to the news organization, the documents showed that Merck knew of reports of depression, including suicidal thoughts, as early as 2009.

However, according to Reuters, the FDA in 2011 granted Merck’s request to only note depression as a potential side effect, without including the risk of suicidal ideation.

The current FDA label notes a small incidence of sexual dysfunction, including decreased libido (1.8% in trials) and erectile dysfunction (1.3%) and mentions depression as a side effect observed during the postmarketing period.

The Canadian label has the same statistics on sexual side effects but is much stronger on mental adverse effects: “Psychiatric disorders: mood alterations and depression, decreased libido that continued after discontinuation of treatment. Mood alterations including depressed mood and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms, and if these occur, the patient should be advised to seek medical advice.”

In the United Kingdom, patients prescribed the drug are given a leaflet, which notes that “Mood alterations such as depressed mood, depression and, less frequently, suicidal thoughts have been reported in patients treated with Propecia,” and advises patients to stop taking the drug if they experience any of those symptoms and to discuss it with their physician.

Public Citizen noted in its lawsuit that French and German drug regulators have sent letters to clinicians advising them to inform patients of the risk of suicidal thoughts and anxiety.

Is there biological plausibility?

To bolster its argument that finasteride has dangerous psychiatric side effects, the advocacy organization cited a study first published in JAMA Dermatology in late 2020 that investigated suicidality and psychological adverse events in patients taking finasteride.

David-Dan Nguyen, MPH, and his colleagues at Brigham and Women’s Hospital in Boston, McGill University, Montreal, and the University of Montreal, examined the VigiBase database and found 356 cases of suicidality and 2,926 psychological adverse events; cases were highest from 2015 to 2019.

They documented what they called a “significant disproportionality signal for suicidality (reporting odds ratio, 1.63; 95% confidence interval, 2.90-4.15) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) with finasteride, especially in younger men and those with alopecia, but not in older men or those with benign prostatic hyperplasia.

The study authors noted that some studies have suggested that men with depression have low levels of the neurosteroid allopregnanolone, which is produced by the 5-alpha reductase enzyme. Finasteride is a 5-alpha reductase inhibitor.

According to Public Citizen’s lawsuit, “The product labeling does not disclose important information about finasteride’s mechanism of action,” and “the drug inhibits multiple steroid hormone pathways that are responsible for the formation of brain neurosteroids that regulate many critical functions in the central nervous system, like sexual function, mood, sleep, cognitive function, the stress response, and motivation.”

Dr. Jacobs said that “there’s a lot of good solid high-quality research, mostly in animals, but also some on humans, showing a plausible link between blocking 5-alpha reductase in the brain, deficiency of neuroactive steroids, and depression.”

The author of an accompanying editorial, Roger S. Ho, MD, MPH, an associate professor in the department of dermatology, New York University, was skeptical. “Without a plausible biological hypothesis pharmacodynamically linking the drug and the reported adverse event, this kind of analysis may lead to false findings,” Dr. Ho said in the editorial about the Nguyen study.

Dr. Ho also wrote that he believed that the lack of a suicidality signal for dutasteride, a drug with a similar mechanism of action, but without as much media attention, “hints at a potential reporting bias unique to finasteride.”

He recommended that clinicians “conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride.”
 

Important medicine, important caveats

Dr. Jacobs said that many of the men who come to him with side effects after taking finasteride have “been blown off by most of the doctors they go to see.”

Urologists dismiss them because their sexual dysfunction is not a gonad issue. They are told that it’s in their head, said Dr. Jacobs, adding that, “it is in their head, but it’s biological.”

The drug’s label advises that sexual side effects disappear when the drug is stopped. “That’s only true most of the time, not all of the time,” said Dr. Jacobs, adding that the persistence of any side effects impacts what he calls a “small subset” of men who take the drug.

“We have treated tens of thousands of patients who have benefited from the medicine and had no side effects,” said Dr. Bernstein. “But there is a lot that’s still not known about it.”

Even so, “baldness in young people is not a benign condition,” he said, adding that it can be socially debilitating. “An 18-year-old with a full head of thick hair who’s totally bald in 3 or 4 years – that can totally change his psyche,” Dr. Bernstein said. Finasteride may be the best option for those young men, and it is an important medication, he said. Does it need to be used more carefully? “Certainly you can’t argue with that,” he commented.

Dr. Bernstein and Dr. Irwig reported no conflicts. Dr. Jacobs disclosed that he is an expert witness for the plaintiffs in a suit against Propecia maker Merck.

A new lawsuit seeking to force the Food and Drug Administration to act on a request to add stricter warnings to finasteride or remove it from the market may rekindle a debate on whether some of the observed side effects from the hair loss drug merit a closer look and, potentially, better counseling and monitoring from clinicians.

The nonprofit advocacy group Public Citizen filed the suit on behalf of the Post-Finasteride Syndrome Foundation (PFSF) in the U.S. District Court for the District of Columbia. The PFSF had filed a citizen’s petition in 2017 that requested that the FDA either take the 1-mg formulation off the market, or add warnings about the potential for erectile dysfunction, depression, and suicidal ideation, among other adverse reactions.

The PFSF has alleged that long-term use of Propecia (and its generic equivalents) can lead to postfinasteride syndrome (PFS), characterized by sexual dysfunction and psycho-neurocognitive symptoms. The symptoms may continue long after men stop taking the drug, according to PFSF.

Public Citizen said the FDA needs to take action in part because U.S. prescriptions of the hair loss formulation “more than doubled from 2015 to 2020,” and online and telemedicine companies such as Hims, Roman, and Keeps “aggressively market and sell generic finasteride for hair loss.” According to GoodRx, a 1-month supply of generic 1-mg tablets costs as little as $8-$10.

Both Canadian and British regulatory authorities have added warnings about depression and suicide to the Propecia label but the FDA has not changed its labeling. An agency spokesperson told this news organization that the “FDA does not comment on the status of pending citizen petitions or on pending litigation.”

Propecia’s developer, Merck, has not responded to several requests for comment from this news organization.

Why some patients develop PFS and others do not is still not understood, but some clinicians said they counsel all patients on the risks of severe and persistent side effects that have been associated with Propecia.

Robert M. Bernstein, MD, of the department of dermatology at Columbia University, New York, and a fellow of the International Society of Hair Restoration Surgery, said that 2%-4% of his patients have some side effects, similar to the original reported incidence, with sexual dysfunction being the most common.

If a man experiences an adverse effect, the drug should be stopped, Dr. Bernstein said in an interview. He noted that “there seems to be a significant increased risk of persistent side effects in people with certain psychiatric conditions, and those people should be counseled carefully before considering the medication.”

“Everybody should be warned that the risk of persistent side effects is real but in the average person it is quite uncommon,” added Dr. Bernstein, founder of Bernstein Medical, a division of Schweiger Dermatology Group focusing on the diagnosis and treatment of hair loss. “I don’t think it should be withdrawn from the market,” he said.

Other countries warn of psychiatric effects

The FDA approved the 1-mg form of finasteride for male pattern hair loss in 1997.

In 2012, the label and the patient insert were updated to state that side effects included less desire for sex, erectile dysfunction, and a decrease in the amount of semen produced, but that those adverse events occurred in less than 2% of men and generally went away in most men who stopped taking the drug.

That label change unleashed a flood of more than 1,000 lawsuits against Merck. The company reportedly settled at least half of them for $4.3 million in 2018. The Superior Court of New Jersey closed out the consolidated class action against Merck in May 2021, noting that all of the cases had been settled or dismissed.

The suits generally accused Merck of not giving adequate warning about sexual side effects, according to an investigation by Reuters. That 2019 special report found that Merck had understated the number of men who experienced sexual side effects and the duration of those symptoms. The news organization also reported that from 2009 to 2018, the FDA received 5,000 reports of sexual or mental health side effects – and sometimes both – in men who took finasteride. Some 350 of the men reported suicidal thoughts, and there were 50 reports of suicide.

Public Citizen’s lawsuit alleges that VigiBase, which is managed by the World Health Organization Collaborating Centre for International Drug Monitoring, lists 378 cases of suicidal ideation, 39 cases of suicide attempt, and 88 cases of completed suicide associated with finasteride use. VigiBase collects data from 153 countries on adverse reactions to medications.

In February 2021, more documents from the class action lawsuits were unsealed in response to a Reuters request. According to the news organization, the documents showed that Merck knew of reports of depression, including suicidal thoughts, as early as 2009.

However, according to Reuters, the FDA in 2011 granted Merck’s request to only note depression as a potential side effect, without including the risk of suicidal ideation.

The current FDA label notes a small incidence of sexual dysfunction, including decreased libido (1.8% in trials) and erectile dysfunction (1.3%) and mentions depression as a side effect observed during the postmarketing period.

The Canadian label has the same statistics on sexual side effects but is much stronger on mental adverse effects: “Psychiatric disorders: mood alterations and depression, decreased libido that continued after discontinuation of treatment. Mood alterations including depressed mood and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms, and if these occur, the patient should be advised to seek medical advice.”

In the United Kingdom, patients prescribed the drug are given a leaflet, which notes that “Mood alterations such as depressed mood, depression and, less frequently, suicidal thoughts have been reported in patients treated with Propecia,” and advises patients to stop taking the drug if they experience any of those symptoms and to discuss it with their physician.

Public Citizen noted in its lawsuit that French and German drug regulators have sent letters to clinicians advising them to inform patients of the risk of suicidal thoughts and anxiety.

Is there biological plausibility?

To bolster its argument that finasteride has dangerous psychiatric side effects, the advocacy organization cited a study first published in JAMA Dermatology in late 2020 that investigated suicidality and psychological adverse events in patients taking finasteride.

David-Dan Nguyen, MPH, and his colleagues at Brigham and Women’s Hospital in Boston, McGill University, Montreal, and the University of Montreal, examined the VigiBase database and found 356 cases of suicidality and 2,926 psychological adverse events; cases were highest from 2015 to 2019.

They documented what they called a “significant disproportionality signal for suicidality (reporting odds ratio, 1.63; 95% confidence interval, 2.90-4.15) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) with finasteride, especially in younger men and those with alopecia, but not in older men or those with benign prostatic hyperplasia.

The study authors noted that some studies have suggested that men with depression have low levels of the neurosteroid allopregnanolone, which is produced by the 5-alpha reductase enzyme. Finasteride is a 5-alpha reductase inhibitor.

According to Public Citizen’s lawsuit, “The product labeling does not disclose important information about finasteride’s mechanism of action,” and “the drug inhibits multiple steroid hormone pathways that are responsible for the formation of brain neurosteroids that regulate many critical functions in the central nervous system, like sexual function, mood, sleep, cognitive function, the stress response, and motivation.”

Dr. Jacobs said that “there’s a lot of good solid high-quality research, mostly in animals, but also some on humans, showing a plausible link between blocking 5-alpha reductase in the brain, deficiency of neuroactive steroids, and depression.”

The author of an accompanying editorial, Roger S. Ho, MD, MPH, an associate professor in the department of dermatology, New York University, was skeptical. “Without a plausible biological hypothesis pharmacodynamically linking the drug and the reported adverse event, this kind of analysis may lead to false findings,” Dr. Ho said in the editorial about the Nguyen study.

Dr. Ho also wrote that he believed that the lack of a suicidality signal for dutasteride, a drug with a similar mechanism of action, but without as much media attention, “hints at a potential reporting bias unique to finasteride.”

He recommended that clinicians “conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride.”
 

Important medicine, important caveats

Dr. Jacobs said that many of the men who come to him with side effects after taking finasteride have “been blown off by most of the doctors they go to see.”

Urologists dismiss them because their sexual dysfunction is not a gonad issue. They are told that it’s in their head, said Dr. Jacobs, adding that, “it is in their head, but it’s biological.”

The drug’s label advises that sexual side effects disappear when the drug is stopped. “That’s only true most of the time, not all of the time,” said Dr. Jacobs, adding that the persistence of any side effects impacts what he calls a “small subset” of men who take the drug.

“We have treated tens of thousands of patients who have benefited from the medicine and had no side effects,” said Dr. Bernstein. “But there is a lot that’s still not known about it.”

Even so, “baldness in young people is not a benign condition,” he said, adding that it can be socially debilitating. “An 18-year-old with a full head of thick hair who’s totally bald in 3 or 4 years – that can totally change his psyche,” Dr. Bernstein said. Finasteride may be the best option for those young men, and it is an important medication, he said. Does it need to be used more carefully? “Certainly you can’t argue with that,” he commented.

Dr. Bernstein and Dr. Irwig reported no conflicts. Dr. Jacobs disclosed that he is an expert witness for the plaintiffs in a suit against Propecia maker Merck.

A new lawsuit seeking to force the Food and Drug Administration to act on a request to add stricter warnings to finasteride or remove it from the market may rekindle a debate on whether some of the observed side effects from the hair loss drug merit a closer look and, potentially, better counseling and monitoring from clinicians.

The nonprofit advocacy group Public Citizen filed the suit on behalf of the Post-Finasteride Syndrome Foundation (PFSF) in the U.S. District Court for the District of Columbia. The PFSF had filed a citizen’s petition in 2017 that requested that the FDA either take the 1-mg formulation off the market, or add warnings about the potential for erectile dysfunction, depression, and suicidal ideation, among other adverse reactions.

The PFSF has alleged that long-term use of Propecia (and its generic equivalents) can lead to postfinasteride syndrome (PFS), characterized by sexual dysfunction and psycho-neurocognitive symptoms. The symptoms may continue long after men stop taking the drug, according to PFSF.

Public Citizen said the FDA needs to take action in part because U.S. prescriptions of the hair loss formulation “more than doubled from 2015 to 2020,” and online and telemedicine companies such as Hims, Roman, and Keeps “aggressively market and sell generic finasteride for hair loss.” According to GoodRx, a 1-month supply of generic 1-mg tablets costs as little as $8-$10.

Both Canadian and British regulatory authorities have added warnings about depression and suicide to the Propecia label but the FDA has not changed its labeling. An agency spokesperson told this news organization that the “FDA does not comment on the status of pending citizen petitions or on pending litigation.”

Propecia’s developer, Merck, has not responded to several requests for comment from this news organization.

Why some patients develop PFS and others do not is still not understood, but some clinicians said they counsel all patients on the risks of severe and persistent side effects that have been associated with Propecia.

Robert M. Bernstein, MD, of the department of dermatology at Columbia University, New York, and a fellow of the International Society of Hair Restoration Surgery, said that 2%-4% of his patients have some side effects, similar to the original reported incidence, with sexual dysfunction being the most common.

If a man experiences an adverse effect, the drug should be stopped, Dr. Bernstein said in an interview. He noted that “there seems to be a significant increased risk of persistent side effects in people with certain psychiatric conditions, and those people should be counseled carefully before considering the medication.”

“Everybody should be warned that the risk of persistent side effects is real but in the average person it is quite uncommon,” added Dr. Bernstein, founder of Bernstein Medical, a division of Schweiger Dermatology Group focusing on the diagnosis and treatment of hair loss. “I don’t think it should be withdrawn from the market,” he said.

Other countries warn of psychiatric effects

The FDA approved the 1-mg form of finasteride for male pattern hair loss in 1997.

In 2012, the label and the patient insert were updated to state that side effects included less desire for sex, erectile dysfunction, and a decrease in the amount of semen produced, but that those adverse events occurred in less than 2% of men and generally went away in most men who stopped taking the drug.

That label change unleashed a flood of more than 1,000 lawsuits against Merck. The company reportedly settled at least half of them for $4.3 million in 2018. The Superior Court of New Jersey closed out the consolidated class action against Merck in May 2021, noting that all of the cases had been settled or dismissed.

The suits generally accused Merck of not giving adequate warning about sexual side effects, according to an investigation by Reuters. That 2019 special report found that Merck had understated the number of men who experienced sexual side effects and the duration of those symptoms. The news organization also reported that from 2009 to 2018, the FDA received 5,000 reports of sexual or mental health side effects – and sometimes both – in men who took finasteride. Some 350 of the men reported suicidal thoughts, and there were 50 reports of suicide.

Public Citizen’s lawsuit alleges that VigiBase, which is managed by the World Health Organization Collaborating Centre for International Drug Monitoring, lists 378 cases of suicidal ideation, 39 cases of suicide attempt, and 88 cases of completed suicide associated with finasteride use. VigiBase collects data from 153 countries on adverse reactions to medications.

In February 2021, more documents from the class action lawsuits were unsealed in response to a Reuters request. According to the news organization, the documents showed that Merck knew of reports of depression, including suicidal thoughts, as early as 2009.

However, according to Reuters, the FDA in 2011 granted Merck’s request to only note depression as a potential side effect, without including the risk of suicidal ideation.

The current FDA label notes a small incidence of sexual dysfunction, including decreased libido (1.8% in trials) and erectile dysfunction (1.3%) and mentions depression as a side effect observed during the postmarketing period.

The Canadian label has the same statistics on sexual side effects but is much stronger on mental adverse effects: “Psychiatric disorders: mood alterations and depression, decreased libido that continued after discontinuation of treatment. Mood alterations including depressed mood and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms, and if these occur, the patient should be advised to seek medical advice.”

In the United Kingdom, patients prescribed the drug are given a leaflet, which notes that “Mood alterations such as depressed mood, depression and, less frequently, suicidal thoughts have been reported in patients treated with Propecia,” and advises patients to stop taking the drug if they experience any of those symptoms and to discuss it with their physician.

Public Citizen noted in its lawsuit that French and German drug regulators have sent letters to clinicians advising them to inform patients of the risk of suicidal thoughts and anxiety.

Is there biological plausibility?

To bolster its argument that finasteride has dangerous psychiatric side effects, the advocacy organization cited a study first published in JAMA Dermatology in late 2020 that investigated suicidality and psychological adverse events in patients taking finasteride.

David-Dan Nguyen, MPH, and his colleagues at Brigham and Women’s Hospital in Boston, McGill University, Montreal, and the University of Montreal, examined the VigiBase database and found 356 cases of suicidality and 2,926 psychological adverse events; cases were highest from 2015 to 2019.

They documented what they called a “significant disproportionality signal for suicidality (reporting odds ratio, 1.63; 95% confidence interval, 2.90-4.15) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) with finasteride, especially in younger men and those with alopecia, but not in older men or those with benign prostatic hyperplasia.

The study authors noted that some studies have suggested that men with depression have low levels of the neurosteroid allopregnanolone, which is produced by the 5-alpha reductase enzyme. Finasteride is a 5-alpha reductase inhibitor.

According to Public Citizen’s lawsuit, “The product labeling does not disclose important information about finasteride’s mechanism of action,” and “the drug inhibits multiple steroid hormone pathways that are responsible for the formation of brain neurosteroids that regulate many critical functions in the central nervous system, like sexual function, mood, sleep, cognitive function, the stress response, and motivation.”

Dr. Jacobs said that “there’s a lot of good solid high-quality research, mostly in animals, but also some on humans, showing a plausible link between blocking 5-alpha reductase in the brain, deficiency of neuroactive steroids, and depression.”

The author of an accompanying editorial, Roger S. Ho, MD, MPH, an associate professor in the department of dermatology, New York University, was skeptical. “Without a plausible biological hypothesis pharmacodynamically linking the drug and the reported adverse event, this kind of analysis may lead to false findings,” Dr. Ho said in the editorial about the Nguyen study.

Dr. Ho also wrote that he believed that the lack of a suicidality signal for dutasteride, a drug with a similar mechanism of action, but without as much media attention, “hints at a potential reporting bias unique to finasteride.”

He recommended that clinicians “conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride.”
 

Important medicine, important caveats

Dr. Jacobs said that many of the men who come to him with side effects after taking finasteride have “been blown off by most of the doctors they go to see.”

Urologists dismiss them because their sexual dysfunction is not a gonad issue. They are told that it’s in their head, said Dr. Jacobs, adding that, “it is in their head, but it’s biological.”

The drug’s label advises that sexual side effects disappear when the drug is stopped. “That’s only true most of the time, not all of the time,” said Dr. Jacobs, adding that the persistence of any side effects impacts what he calls a “small subset” of men who take the drug.

“We have treated tens of thousands of patients who have benefited from the medicine and had no side effects,” said Dr. Bernstein. “But there is a lot that’s still not known about it.”

Even so, “baldness in young people is not a benign condition,” he said, adding that it can be socially debilitating. “An 18-year-old with a full head of thick hair who’s totally bald in 3 or 4 years – that can totally change his psyche,” Dr. Bernstein said. Finasteride may be the best option for those young men, and it is an important medication, he said. Does it need to be used more carefully? “Certainly you can’t argue with that,” he commented.

Dr. Bernstein and Dr. Irwig reported no conflicts. Dr. Jacobs disclosed that he is an expert witness for the plaintiffs in a suit against Propecia maker Merck.

On Sept. 5, Rashid Buttar, DO, posted on Twitter that COVID-19 “was a planned operation” and shared an article alleging that most people who got the COVID vaccine would be dead by 2025.

His statement is a recent example in what has been a steady stream of spurious claims surrounding the COVID vaccines and treatments that swirl around the public consciousness. Others include testimony in June by Sherri Jane Tenpenny, DO, before Ohio state legislators that the vaccine could cause people to become magnetized. Clips from the hearing went viral on the Internet. On April 9, 2020, Joseph Mercola, DO, posted a video titled “Could hydrogen peroxide treat coronavirus?” which was shared more than 4,600 times. In the video, Dr. Mercola said inhaling hydrogen peroxide through a nebulizer could prevent or cure COVID.

These physicians are identified as members of the “Disinformation Dozen,” a group of top superspreaders of COVID vaccine misinformation on social media, according to a 2021 report by the nonprofit Center for Countering Digital Hate. The report, based on an analysis of antivaccine content on social media platforms, found that 12 people were responsible for 65% of it. The group is composed of physicians, antivaccine activists, and people known for promoting alternative medicine.

The physician voices are of particular concern because their medical credentials lend credence to their unproven, often dangerous pronouncements. All three continue to hold medical licenses and have not faced consequences for their COVID-related statements.

But leaders of professional medical organizations increasingly are calling for that to change and urging medical oversight boards to take more aggressive action.

In July, the Federation of State Medical Boards, the national umbrella organization for the state-based boards, issued a statement making clear that doctors who generate and spread COVID misinformation could be subject to disciplinary action, including the suspension or revocation of their licenses. The American Board of Family Medicine, American Board of Internal Medicine, and American Board of Pediatrics issued a joint statement Sept. 9 in support of the state boards’ position, warning that “such unethical or unprofessional conduct may prompt their respective board to take action that could put their certification at risk.”

And the superspreaders identified by the center’s report are not alone. KHN identified 20 other doctors who have made false or misleading claims about COVID by combing through published fact checks and other news coverage.

For example, at an Indiana school board meeting in August, Dan Stock, MD, claimed the surge in covid cases this summer was due to “antibody mediated viral enhancement” from people receiving covid vaccines. PolitiFact rated his claim “Pants on Fire” false.

Stella Immanuel, MD, a member of a group America’s Frontline Doctors, which has consistently made false statements about COVID, said in a video that went viral in July 2020 that masks weren’t needed because covid could be cured by hydroxychloroquine. Dr. Immanuel’s website currently promotes a set of vitamins, as well as hydroxychloroquine and ivermectin, as COVID treatments.

Two of the doctors mentioned by name in this article responded to requests for comment. Dr. Mercola offered documents to rebut criticisms of his hydrogen peroxide COVID treatment and took issue with the center’s “Disinformation Dozen” report methodology. Dr. Buttar defended his positions, saying via email that “the science is clear and anyone who contests it, has a suspect agenda at best and/or lacks a moral compass.” He also pointed to data from the Centers for Disease Control and Prevention’s Vaccine Adverse Event Recording System, considered inconclusive by many experts.

Since the onset of the COVID pandemic, misinformation has been widespread on social media platforms. And many experts blame it for undermining efforts to curb the coronavirus’s spread. A recent poll showed that more than 50% of Americans who won’t get vaccinated cited conspiracy theories as their reasons – for example, saying the vaccines cause infertility or alter DNA.

Some physicians have gained notoriety by embracing COVID-related fringe ideas, quack treatments and falsehoods via social media, conservative talk shows, and even in person with patients. Whether promoting the use of ivermectin, an antiparasitic drug for animals, or a mix of vitamins to treat COVID, doctors’ words can be especially powerful. Public opinion polls consistently show that Americans have high trust in doctors.

“There is a sense of credibility that comes with being a doctor,” said Rachel Moran, PhD, a researcher who studies COVID misinformation at the University of Washington. “There is also a sense they have access to insider info that we don’t. This is a very confusing time, and it can seem that if anyone knows what I should be doing in this situation, it’s a doctor.”

While COVID is a novel and complicated infectious disease, physicians spreading misinformation generally have no particular expertise in infectious diseases. Scott Atlas, MD, who endorsed former President Donald Trump’s unproven statements about the course of the pandemic, is a radiation oncologist.

Traditionally, the responsibility of policing physicians has fallen to state medical boards. Beyond overseeing the licensing process, these panels investigate complaints about doctors and discipline those who engage in unethical, unprofessional or, in extreme cases, criminal activity. Any member of the public can submit a complaint about a physician.

“The boards are relatively slow and weak and it’s a long, slow process to pull somebody’s license,” said Arthur Caplan, PhD, founding head of the department of medical ethics at New York University. “In many states, they have their hands full with doctors who have committed felonies, doctors who are molesting their patients. Keeping an eye on misinformation is somewhat down on the priority list.”

To date, only two doctors have reportedly faced such sanctions. In Oregon, Steven LaTulippe, MD, had his license suspended in December 2020 for refusing to wear a face mask at his clinic and telling patients that masks were ineffective in curbing the spread of COVID, and even dangerous. Thomas Cowan, MD, a San Francisco physician who posted a YouTube video that went viral in March 2020 stating that 5G networks cause COVID, voluntarily surrendered his medical license to California’s medical board in February 2021.

Humayun Chaudhry, DO, president of the Federation of State Medical Boards, however, said it’s possible some doctors could already be the subject of inquiries and investigations, since these actions are not made public until sanctions are handed down.

KHN reached out to the medical and osteopathic boards of all 50 states and the District of Columbia to see if they had received COVID misinformation complaints. Of the 43 that responded, only a handful shared specifics.

During a 1-week period in August, Kansas’ medical board received six such complaints. In all, the state has received 35 complaints against 20 licensees about spreading covid misinformation on social media and in person. Indiana has received about 30 in the past year. South Carolina said it had about 10 since January. Rhode Island didn’t share the number of complaints but said it has taken disciplinary action against one doctor for spreading misinformation, though it hasn’t moved to suspend his license. (The disciplinary measures include a fine, a reprimand on the doctor’s record and a mandate to complete an ethics course.) Five states said they had received only a couple, and 11 states reported receiving no complaints regarding COVID misinformation.

Confidentiality laws in 13 states prevented those boards from sharing information about complaints.

Social media companies have also been slow to take action. Some doctors’ accounts – specifically those among the Disinformation Dozen – have been suspended, but others are still active and posting misinformation.

Imran Ahmed, CEO of the Center for Countering Digital Hate, said social media platforms often don’t consistently apply their rules against spreading misinformation.

“Even when it’s the same companies, Facebook will sometimes take posts down, but Instagram will not,” Mr. Ahmed said, referring to Facebook’s ownership of Instagram. “It goes to show their piecemeal, ineffective approach to enforcing their own rules.”

A Facebook spokesperson said the company has removed over 3,000 accounts, pages and groups for repeatedly violating COVID and vaccine misinformation policies since the beginning of the pandemic. Dr. Buttar’s Facebook and Instagram pages and Tenpenny’s Facebook page have been removed, while Dr. Mercola’s Facebook posts have been demoted, which means fewer people will see them. Dr. Tenpenny and Dr. Mercola still have Instagram accounts.

Part of the challenge may be that these doctors sometimes present scientific opinions that aren’t mainstream but are viewed as potentially valid by some of their colleagues.

“It can be difficult to prove that what is being said is outside the range of scientific and medical consensus,” said Dr. Caplan. “The doctors who were advising Trump – like Scott Atlas – recommended herd immunity. That was far from the consensus of epidemiologists, but you couldn’t get a board to take his license away because it was a fringe opinion.”

Even if these physicians don’t face consequences, it is likely, experts said, that the public health will.

“Medical misinformation doesn’t just result in people making bad personal and community health choices, but it also divides communities and families, leaving an emotional toll,” said Dr. Moran. “Misinformation narratives have real sticking power and impact people’s ability to make safe health choices.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

On Sept. 5, Rashid Buttar, DO, posted on Twitter that COVID-19 “was a planned operation” and shared an article alleging that most people who got the COVID vaccine would be dead by 2025.

His statement is a recent example in what has been a steady stream of spurious claims surrounding the COVID vaccines and treatments that swirl around the public consciousness. Others include testimony in June by Sherri Jane Tenpenny, DO, before Ohio state legislators that the vaccine could cause people to become magnetized. Clips from the hearing went viral on the Internet. On April 9, 2020, Joseph Mercola, DO, posted a video titled “Could hydrogen peroxide treat coronavirus?” which was shared more than 4,600 times. In the video, Dr. Mercola said inhaling hydrogen peroxide through a nebulizer could prevent or cure COVID.

These physicians are identified as members of the “Disinformation Dozen,” a group of top superspreaders of COVID vaccine misinformation on social media, according to a 2021 report by the nonprofit Center for Countering Digital Hate. The report, based on an analysis of antivaccine content on social media platforms, found that 12 people were responsible for 65% of it. The group is composed of physicians, antivaccine activists, and people known for promoting alternative medicine.

The physician voices are of particular concern because their medical credentials lend credence to their unproven, often dangerous pronouncements. All three continue to hold medical licenses and have not faced consequences for their COVID-related statements.

But leaders of professional medical organizations increasingly are calling for that to change and urging medical oversight boards to take more aggressive action.

In July, the Federation of State Medical Boards, the national umbrella organization for the state-based boards, issued a statement making clear that doctors who generate and spread COVID misinformation could be subject to disciplinary action, including the suspension or revocation of their licenses. The American Board of Family Medicine, American Board of Internal Medicine, and American Board of Pediatrics issued a joint statement Sept. 9 in support of the state boards’ position, warning that “such unethical or unprofessional conduct may prompt their respective board to take action that could put their certification at risk.”

And the superspreaders identified by the center’s report are not alone. KHN identified 20 other doctors who have made false or misleading claims about COVID by combing through published fact checks and other news coverage.

For example, at an Indiana school board meeting in August, Dan Stock, MD, claimed the surge in covid cases this summer was due to “antibody mediated viral enhancement” from people receiving covid vaccines. PolitiFact rated his claim “Pants on Fire” false.

Stella Immanuel, MD, a member of a group America’s Frontline Doctors, which has consistently made false statements about COVID, said in a video that went viral in July 2020 that masks weren’t needed because covid could be cured by hydroxychloroquine. Dr. Immanuel’s website currently promotes a set of vitamins, as well as hydroxychloroquine and ivermectin, as COVID treatments.

Two of the doctors mentioned by name in this article responded to requests for comment. Dr. Mercola offered documents to rebut criticisms of his hydrogen peroxide COVID treatment and took issue with the center’s “Disinformation Dozen” report methodology. Dr. Buttar defended his positions, saying via email that “the science is clear and anyone who contests it, has a suspect agenda at best and/or lacks a moral compass.” He also pointed to data from the Centers for Disease Control and Prevention’s Vaccine Adverse Event Recording System, considered inconclusive by many experts.

Since the onset of the COVID pandemic, misinformation has been widespread on social media platforms. And many experts blame it for undermining efforts to curb the coronavirus’s spread. A recent poll showed that more than 50% of Americans who won’t get vaccinated cited conspiracy theories as their reasons – for example, saying the vaccines cause infertility or alter DNA.

Some physicians have gained notoriety by embracing COVID-related fringe ideas, quack treatments and falsehoods via social media, conservative talk shows, and even in person with patients. Whether promoting the use of ivermectin, an antiparasitic drug for animals, or a mix of vitamins to treat COVID, doctors’ words can be especially powerful. Public opinion polls consistently show that Americans have high trust in doctors.

“There is a sense of credibility that comes with being a doctor,” said Rachel Moran, PhD, a researcher who studies COVID misinformation at the University of Washington. “There is also a sense they have access to insider info that we don’t. This is a very confusing time, and it can seem that if anyone knows what I should be doing in this situation, it’s a doctor.”

While COVID is a novel and complicated infectious disease, physicians spreading misinformation generally have no particular expertise in infectious diseases. Scott Atlas, MD, who endorsed former President Donald Trump’s unproven statements about the course of the pandemic, is a radiation oncologist.

Traditionally, the responsibility of policing physicians has fallen to state medical boards. Beyond overseeing the licensing process, these panels investigate complaints about doctors and discipline those who engage in unethical, unprofessional or, in extreme cases, criminal activity. Any member of the public can submit a complaint about a physician.

“The boards are relatively slow and weak and it’s a long, slow process to pull somebody’s license,” said Arthur Caplan, PhD, founding head of the department of medical ethics at New York University. “In many states, they have their hands full with doctors who have committed felonies, doctors who are molesting their patients. Keeping an eye on misinformation is somewhat down on the priority list.”

To date, only two doctors have reportedly faced such sanctions. In Oregon, Steven LaTulippe, MD, had his license suspended in December 2020 for refusing to wear a face mask at his clinic and telling patients that masks were ineffective in curbing the spread of COVID, and even dangerous. Thomas Cowan, MD, a San Francisco physician who posted a YouTube video that went viral in March 2020 stating that 5G networks cause COVID, voluntarily surrendered his medical license to California’s medical board in February 2021.

Humayun Chaudhry, DO, president of the Federation of State Medical Boards, however, said it’s possible some doctors could already be the subject of inquiries and investigations, since these actions are not made public until sanctions are handed down.

KHN reached out to the medical and osteopathic boards of all 50 states and the District of Columbia to see if they had received COVID misinformation complaints. Of the 43 that responded, only a handful shared specifics.

During a 1-week period in August, Kansas’ medical board received six such complaints. In all, the state has received 35 complaints against 20 licensees about spreading covid misinformation on social media and in person. Indiana has received about 30 in the past year. South Carolina said it had about 10 since January. Rhode Island didn’t share the number of complaints but said it has taken disciplinary action against one doctor for spreading misinformation, though it hasn’t moved to suspend his license. (The disciplinary measures include a fine, a reprimand on the doctor’s record and a mandate to complete an ethics course.) Five states said they had received only a couple, and 11 states reported receiving no complaints regarding COVID misinformation.

Confidentiality laws in 13 states prevented those boards from sharing information about complaints.

Social media companies have also been slow to take action. Some doctors’ accounts – specifically those among the Disinformation Dozen – have been suspended, but others are still active and posting misinformation.

Imran Ahmed, CEO of the Center for Countering Digital Hate, said social media platforms often don’t consistently apply their rules against spreading misinformation.

“Even when it’s the same companies, Facebook will sometimes take posts down, but Instagram will not,” Mr. Ahmed said, referring to Facebook’s ownership of Instagram. “It goes to show their piecemeal, ineffective approach to enforcing their own rules.”

A Facebook spokesperson said the company has removed over 3,000 accounts, pages and groups for repeatedly violating COVID and vaccine misinformation policies since the beginning of the pandemic. Dr. Buttar’s Facebook and Instagram pages and Tenpenny’s Facebook page have been removed, while Dr. Mercola’s Facebook posts have been demoted, which means fewer people will see them. Dr. Tenpenny and Dr. Mercola still have Instagram accounts.

Part of the challenge may be that these doctors sometimes present scientific opinions that aren’t mainstream but are viewed as potentially valid by some of their colleagues.

“It can be difficult to prove that what is being said is outside the range of scientific and medical consensus,” said Dr. Caplan. “The doctors who were advising Trump – like Scott Atlas – recommended herd immunity. That was far from the consensus of epidemiologists, but you couldn’t get a board to take his license away because it was a fringe opinion.”

Even if these physicians don’t face consequences, it is likely, experts said, that the public health will.

“Medical misinformation doesn’t just result in people making bad personal and community health choices, but it also divides communities and families, leaving an emotional toll,” said Dr. Moran. “Misinformation narratives have real sticking power and impact people’s ability to make safe health choices.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

On Sept. 5, Rashid Buttar, DO, posted on Twitter that COVID-19 “was a planned operation” and shared an article alleging that most people who got the COVID vaccine would be dead by 2025.

His statement is a recent example in what has been a steady stream of spurious claims surrounding the COVID vaccines and treatments that swirl around the public consciousness. Others include testimony in June by Sherri Jane Tenpenny, DO, before Ohio state legislators that the vaccine could cause people to become magnetized. Clips from the hearing went viral on the Internet. On April 9, 2020, Joseph Mercola, DO, posted a video titled “Could hydrogen peroxide treat coronavirus?” which was shared more than 4,600 times. In the video, Dr. Mercola said inhaling hydrogen peroxide through a nebulizer could prevent or cure COVID.

These physicians are identified as members of the “Disinformation Dozen,” a group of top superspreaders of COVID vaccine misinformation on social media, according to a 2021 report by the nonprofit Center for Countering Digital Hate. The report, based on an analysis of antivaccine content on social media platforms, found that 12 people were responsible for 65% of it. The group is composed of physicians, antivaccine activists, and people known for promoting alternative medicine.

The physician voices are of particular concern because their medical credentials lend credence to their unproven, often dangerous pronouncements. All three continue to hold medical licenses and have not faced consequences for their COVID-related statements.

But leaders of professional medical organizations increasingly are calling for that to change and urging medical oversight boards to take more aggressive action.

In July, the Federation of State Medical Boards, the national umbrella organization for the state-based boards, issued a statement making clear that doctors who generate and spread COVID misinformation could be subject to disciplinary action, including the suspension or revocation of their licenses. The American Board of Family Medicine, American Board of Internal Medicine, and American Board of Pediatrics issued a joint statement Sept. 9 in support of the state boards’ position, warning that “such unethical or unprofessional conduct may prompt their respective board to take action that could put their certification at risk.”

And the superspreaders identified by the center’s report are not alone. KHN identified 20 other doctors who have made false or misleading claims about COVID by combing through published fact checks and other news coverage.

For example, at an Indiana school board meeting in August, Dan Stock, MD, claimed the surge in covid cases this summer was due to “antibody mediated viral enhancement” from people receiving covid vaccines. PolitiFact rated his claim “Pants on Fire” false.

Stella Immanuel, MD, a member of a group America’s Frontline Doctors, which has consistently made false statements about COVID, said in a video that went viral in July 2020 that masks weren’t needed because covid could be cured by hydroxychloroquine. Dr. Immanuel’s website currently promotes a set of vitamins, as well as hydroxychloroquine and ivermectin, as COVID treatments.

Two of the doctors mentioned by name in this article responded to requests for comment. Dr. Mercola offered documents to rebut criticisms of his hydrogen peroxide COVID treatment and took issue with the center’s “Disinformation Dozen” report methodology. Dr. Buttar defended his positions, saying via email that “the science is clear and anyone who contests it, has a suspect agenda at best and/or lacks a moral compass.” He also pointed to data from the Centers for Disease Control and Prevention’s Vaccine Adverse Event Recording System, considered inconclusive by many experts.

Since the onset of the COVID pandemic, misinformation has been widespread on social media platforms. And many experts blame it for undermining efforts to curb the coronavirus’s spread. A recent poll showed that more than 50% of Americans who won’t get vaccinated cited conspiracy theories as their reasons – for example, saying the vaccines cause infertility or alter DNA.

Some physicians have gained notoriety by embracing COVID-related fringe ideas, quack treatments and falsehoods via social media, conservative talk shows, and even in person with patients. Whether promoting the use of ivermectin, an antiparasitic drug for animals, or a mix of vitamins to treat COVID, doctors’ words can be especially powerful. Public opinion polls consistently show that Americans have high trust in doctors.

“There is a sense of credibility that comes with being a doctor,” said Rachel Moran, PhD, a researcher who studies COVID misinformation at the University of Washington. “There is also a sense they have access to insider info that we don’t. This is a very confusing time, and it can seem that if anyone knows what I should be doing in this situation, it’s a doctor.”

While COVID is a novel and complicated infectious disease, physicians spreading misinformation generally have no particular expertise in infectious diseases. Scott Atlas, MD, who endorsed former President Donald Trump’s unproven statements about the course of the pandemic, is a radiation oncologist.

Traditionally, the responsibility of policing physicians has fallen to state medical boards. Beyond overseeing the licensing process, these panels investigate complaints about doctors and discipline those who engage in unethical, unprofessional or, in extreme cases, criminal activity. Any member of the public can submit a complaint about a physician.

“The boards are relatively slow and weak and it’s a long, slow process to pull somebody’s license,” said Arthur Caplan, PhD, founding head of the department of medical ethics at New York University. “In many states, they have their hands full with doctors who have committed felonies, doctors who are molesting their patients. Keeping an eye on misinformation is somewhat down on the priority list.”

To date, only two doctors have reportedly faced such sanctions. In Oregon, Steven LaTulippe, MD, had his license suspended in December 2020 for refusing to wear a face mask at his clinic and telling patients that masks were ineffective in curbing the spread of COVID, and even dangerous. Thomas Cowan, MD, a San Francisco physician who posted a YouTube video that went viral in March 2020 stating that 5G networks cause COVID, voluntarily surrendered his medical license to California’s medical board in February 2021.

Humayun Chaudhry, DO, president of the Federation of State Medical Boards, however, said it’s possible some doctors could already be the subject of inquiries and investigations, since these actions are not made public until sanctions are handed down.

KHN reached out to the medical and osteopathic boards of all 50 states and the District of Columbia to see if they had received COVID misinformation complaints. Of the 43 that responded, only a handful shared specifics.

During a 1-week period in August, Kansas’ medical board received six such complaints. In all, the state has received 35 complaints against 20 licensees about spreading covid misinformation on social media and in person. Indiana has received about 30 in the past year. South Carolina said it had about 10 since January. Rhode Island didn’t share the number of complaints but said it has taken disciplinary action against one doctor for spreading misinformation, though it hasn’t moved to suspend his license. (The disciplinary measures include a fine, a reprimand on the doctor’s record and a mandate to complete an ethics course.) Five states said they had received only a couple, and 11 states reported receiving no complaints regarding COVID misinformation.

Confidentiality laws in 13 states prevented those boards from sharing information about complaints.

Social media companies have also been slow to take action. Some doctors’ accounts – specifically those among the Disinformation Dozen – have been suspended, but others are still active and posting misinformation.

Imran Ahmed, CEO of the Center for Countering Digital Hate, said social media platforms often don’t consistently apply their rules against spreading misinformation.

“Even when it’s the same companies, Facebook will sometimes take posts down, but Instagram will not,” Mr. Ahmed said, referring to Facebook’s ownership of Instagram. “It goes to show their piecemeal, ineffective approach to enforcing their own rules.”

A Facebook spokesperson said the company has removed over 3,000 accounts, pages and groups for repeatedly violating COVID and vaccine misinformation policies since the beginning of the pandemic. Dr. Buttar’s Facebook and Instagram pages and Tenpenny’s Facebook page have been removed, while Dr. Mercola’s Facebook posts have been demoted, which means fewer people will see them. Dr. Tenpenny and Dr. Mercola still have Instagram accounts.

Part of the challenge may be that these doctors sometimes present scientific opinions that aren’t mainstream but are viewed as potentially valid by some of their colleagues.

“It can be difficult to prove that what is being said is outside the range of scientific and medical consensus,” said Dr. Caplan. “The doctors who were advising Trump – like Scott Atlas – recommended herd immunity. That was far from the consensus of epidemiologists, but you couldn’t get a board to take his license away because it was a fringe opinion.”

Even if these physicians don’t face consequences, it is likely, experts said, that the public health will.

“Medical misinformation doesn’t just result in people making bad personal and community health choices, but it also divides communities and families, leaving an emotional toll,” said Dr. Moran. “Misinformation narratives have real sticking power and impact people’s ability to make safe health choices.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Basal cell carcinomas (BCCs), the most common form of skin cancer, are generally slow-growing tumors that occur in older patients.

Given the low rates of metastasis and mortality associated with BCC, some patients do not require treatment. However, there have been no evidence-based recommendations on who may benefit from a watch-and-wait approach.

Now, a study published on Sept. 8 in JAMA Dermatology sheds light on which patients with BCC may be appropriate candidates for watchful waiting.

The investigators found that, for older people with low-grade BCCs and limited life expectancy, the risks associated with surgery – bleeding, infection, and wound dehiscence – appeared to outweigh the advantages. According to the authors, these patients “might not live long enough to benefit from treatment.”

This finding mirrors oncologists’ observations regarding low-risk prostate cancer, for which watchful waiting is now the standard of care.

“At present, however, procedure rates [for patients with BCC] increase with age, and many basal cell carcinomas are treated surgically regardless of a patient’s life expectancy,” Eleni Linos, MD, PhD, professor of dermatology at Stanford (Calif.) University, and Mary-Margaret Chren, MD, chair of dermatology at Vanderbilt University, Nashville, Tenn., write in a viewpoint article published in August in JAMA Internal Medicine.

Considering the current treatment patterns for BCC, patients would “benefit from the existence of an evidence-based standard of care that includes active surveillance,” Mackenzie Wehner, MD, assistant professor at MD Anderson Cancer Center, Houston, Tex., writes in an editorial that accompanies the article in JAMA Dermatology.
 

Insights from the Dutch study

The article in JAMA Dermatology presents a cohort study conducted at Radboud University Medical Center in Nijmegen, the Netherlands. The study included 89 patients who were managed with watchful waiting. The patients received no treatment for at least 3 months following their diagnoses.

The median age of the patients was 83 years. The patients had a total of 280 BCCs. The median initial diameter of the BCCs was 9.5 mm. Just over half of the patients were men, and about half of the BCCs were in the head and neck region.

The median follow-up was 9 months; the maximum follow-up was 6.5 years. Remarkably, the investigators say, more than half the tumors (53.2%) did not grow, and some even shrank. The majority of patients were asymptomatic at presentation, and fewer than 10% developed new symptoms, such as bleeding and itching, during follow-up.

Among the tumors that did grow, 70% were low-risk superficial/nodular tumors, which only increased in size by an estimated 1.06 mm over a year. Thirty percent were higher-risk micronodular/infiltrative tumors, which grew an estimated 4.46 mm over a 12-month period.

About two-thirds of patients eventually chose to have at least one of their BCCs removed after a median of about 7 months. Only three BCCs (2.8%) needed more extensive surgery – reconstructive surgery, rather than primary closure, for instance – than would have been necessary with an earlier excision.

No deaths from BCC were reported in the study.

The investigators tracked the reasons patients opted for watchful waiting. Many understood that their tumors likely would not cause problems in their remaining years. Others prioritized dealing with more pressing health or family problems. Logistics came into play for some, such as not having reliable transportation for hospital visits.

“In patients with [limited life expectancy] and asymptomatic low-risk tumors, [watchful waiting] should be discussed as a potentially appropriate approach,” the investigators, led by Marieke E. C. van Winden, MD, a dermatology resident at Radboud University, conclude.

For patients who wish to pursue a watchful waiting approach, the Dutch team recommends conducting follow-up visits every 3-6 months to see whether patients wish to continue with watchful waiting and to determine whether the risk-to-benefit ratio has shifted.

These recommendations are in line with criteria Dr. Linos and Dr. Chren propose in their viewpoint article in JAMA Internal Medicine. They characterize low-risk BCCs as asymptomatic, smaller than 1 cm in diameter, and located on the trunk or extremities in immunocompetent patients. They note that details regarding active surveillance for BCCs need to be worked out.

“Active surveillance should be studied as a management option because it is supported by the available evidence, congruent with the care of other low-risk cancers, and in accord with principles of shared decision-making,” Dr. Linos and Dr. Chren write.

No funding source was reported. Dr. Wehner, Dr. van Winden, Dr. Linos, and Dr. Chren have disclosed no relevant financial relationships. Two of Dr. van Winden’s coauthors report ties to several companies, including Sanofi Genzyme, AbbVie, Novartis, and Janssen.

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

Basal cell carcinomas (BCCs), the most common form of skin cancer, are generally slow-growing tumors that occur in older patients.

Given the low rates of metastasis and mortality associated with BCC, some patients do not require treatment. However, there have been no evidence-based recommendations on who may benefit from a watch-and-wait approach.

Now, a study published on Sept. 8 in JAMA Dermatology sheds light on which patients with BCC may be appropriate candidates for watchful waiting.

The investigators found that, for older people with low-grade BCCs and limited life expectancy, the risks associated with surgery – bleeding, infection, and wound dehiscence – appeared to outweigh the advantages. According to the authors, these patients “might not live long enough to benefit from treatment.”

This finding mirrors oncologists’ observations regarding low-risk prostate cancer, for which watchful waiting is now the standard of care.

“At present, however, procedure rates [for patients with BCC] increase with age, and many basal cell carcinomas are treated surgically regardless of a patient’s life expectancy,” Eleni Linos, MD, PhD, professor of dermatology at Stanford (Calif.) University, and Mary-Margaret Chren, MD, chair of dermatology at Vanderbilt University, Nashville, Tenn., write in a viewpoint article published in August in JAMA Internal Medicine.

Considering the current treatment patterns for BCC, patients would “benefit from the existence of an evidence-based standard of care that includes active surveillance,” Mackenzie Wehner, MD, assistant professor at MD Anderson Cancer Center, Houston, Tex., writes in an editorial that accompanies the article in JAMA Dermatology.
 

Insights from the Dutch study

The article in JAMA Dermatology presents a cohort study conducted at Radboud University Medical Center in Nijmegen, the Netherlands. The study included 89 patients who were managed with watchful waiting. The patients received no treatment for at least 3 months following their diagnoses.

The median age of the patients was 83 years. The patients had a total of 280 BCCs. The median initial diameter of the BCCs was 9.5 mm. Just over half of the patients were men, and about half of the BCCs were in the head and neck region.

The median follow-up was 9 months; the maximum follow-up was 6.5 years. Remarkably, the investigators say, more than half the tumors (53.2%) did not grow, and some even shrank. The majority of patients were asymptomatic at presentation, and fewer than 10% developed new symptoms, such as bleeding and itching, during follow-up.

Among the tumors that did grow, 70% were low-risk superficial/nodular tumors, which only increased in size by an estimated 1.06 mm over a year. Thirty percent were higher-risk micronodular/infiltrative tumors, which grew an estimated 4.46 mm over a 12-month period.

About two-thirds of patients eventually chose to have at least one of their BCCs removed after a median of about 7 months. Only three BCCs (2.8%) needed more extensive surgery – reconstructive surgery, rather than primary closure, for instance – than would have been necessary with an earlier excision.

No deaths from BCC were reported in the study.

The investigators tracked the reasons patients opted for watchful waiting. Many understood that their tumors likely would not cause problems in their remaining years. Others prioritized dealing with more pressing health or family problems. Logistics came into play for some, such as not having reliable transportation for hospital visits.

“In patients with [limited life expectancy] and asymptomatic low-risk tumors, [watchful waiting] should be discussed as a potentially appropriate approach,” the investigators, led by Marieke E. C. van Winden, MD, a dermatology resident at Radboud University, conclude.

For patients who wish to pursue a watchful waiting approach, the Dutch team recommends conducting follow-up visits every 3-6 months to see whether patients wish to continue with watchful waiting and to determine whether the risk-to-benefit ratio has shifted.

These recommendations are in line with criteria Dr. Linos and Dr. Chren propose in their viewpoint article in JAMA Internal Medicine. They characterize low-risk BCCs as asymptomatic, smaller than 1 cm in diameter, and located on the trunk or extremities in immunocompetent patients. They note that details regarding active surveillance for BCCs need to be worked out.

“Active surveillance should be studied as a management option because it is supported by the available evidence, congruent with the care of other low-risk cancers, and in accord with principles of shared decision-making,” Dr. Linos and Dr. Chren write.

No funding source was reported. Dr. Wehner, Dr. van Winden, Dr. Linos, and Dr. Chren have disclosed no relevant financial relationships. Two of Dr. van Winden’s coauthors report ties to several companies, including Sanofi Genzyme, AbbVie, Novartis, and Janssen.

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

Basal cell carcinomas (BCCs), the most common form of skin cancer, are generally slow-growing tumors that occur in older patients.

Given the low rates of metastasis and mortality associated with BCC, some patients do not require treatment. However, there have been no evidence-based recommendations on who may benefit from a watch-and-wait approach.

Now, a study published on Sept. 8 in JAMA Dermatology sheds light on which patients with BCC may be appropriate candidates for watchful waiting.

The investigators found that, for older people with low-grade BCCs and limited life expectancy, the risks associated with surgery – bleeding, infection, and wound dehiscence – appeared to outweigh the advantages. According to the authors, these patients “might not live long enough to benefit from treatment.”

This finding mirrors oncologists’ observations regarding low-risk prostate cancer, for which watchful waiting is now the standard of care.

“At present, however, procedure rates [for patients with BCC] increase with age, and many basal cell carcinomas are treated surgically regardless of a patient’s life expectancy,” Eleni Linos, MD, PhD, professor of dermatology at Stanford (Calif.) University, and Mary-Margaret Chren, MD, chair of dermatology at Vanderbilt University, Nashville, Tenn., write in a viewpoint article published in August in JAMA Internal Medicine.

Considering the current treatment patterns for BCC, patients would “benefit from the existence of an evidence-based standard of care that includes active surveillance,” Mackenzie Wehner, MD, assistant professor at MD Anderson Cancer Center, Houston, Tex., writes in an editorial that accompanies the article in JAMA Dermatology.
 

Insights from the Dutch study

The article in JAMA Dermatology presents a cohort study conducted at Radboud University Medical Center in Nijmegen, the Netherlands. The study included 89 patients who were managed with watchful waiting. The patients received no treatment for at least 3 months following their diagnoses.

The median age of the patients was 83 years. The patients had a total of 280 BCCs. The median initial diameter of the BCCs was 9.5 mm. Just over half of the patients were men, and about half of the BCCs were in the head and neck region.

The median follow-up was 9 months; the maximum follow-up was 6.5 years. Remarkably, the investigators say, more than half the tumors (53.2%) did not grow, and some even shrank. The majority of patients were asymptomatic at presentation, and fewer than 10% developed new symptoms, such as bleeding and itching, during follow-up.

Among the tumors that did grow, 70% were low-risk superficial/nodular tumors, which only increased in size by an estimated 1.06 mm over a year. Thirty percent were higher-risk micronodular/infiltrative tumors, which grew an estimated 4.46 mm over a 12-month period.

About two-thirds of patients eventually chose to have at least one of their BCCs removed after a median of about 7 months. Only three BCCs (2.8%) needed more extensive surgery – reconstructive surgery, rather than primary closure, for instance – than would have been necessary with an earlier excision.

No deaths from BCC were reported in the study.

The investigators tracked the reasons patients opted for watchful waiting. Many understood that their tumors likely would not cause problems in their remaining years. Others prioritized dealing with more pressing health or family problems. Logistics came into play for some, such as not having reliable transportation for hospital visits.

“In patients with [limited life expectancy] and asymptomatic low-risk tumors, [watchful waiting] should be discussed as a potentially appropriate approach,” the investigators, led by Marieke E. C. van Winden, MD, a dermatology resident at Radboud University, conclude.

For patients who wish to pursue a watchful waiting approach, the Dutch team recommends conducting follow-up visits every 3-6 months to see whether patients wish to continue with watchful waiting and to determine whether the risk-to-benefit ratio has shifted.

These recommendations are in line with criteria Dr. Linos and Dr. Chren propose in their viewpoint article in JAMA Internal Medicine. They characterize low-risk BCCs as asymptomatic, smaller than 1 cm in diameter, and located on the trunk or extremities in immunocompetent patients. They note that details regarding active surveillance for BCCs need to be worked out.

“Active surveillance should be studied as a management option because it is supported by the available evidence, congruent with the care of other low-risk cancers, and in accord with principles of shared decision-making,” Dr. Linos and Dr. Chren write.

No funding source was reported. Dr. Wehner, Dr. van Winden, Dr. Linos, and Dr. Chren have disclosed no relevant financial relationships. Two of Dr. van Winden’s coauthors report ties to several companies, including Sanofi Genzyme, AbbVie, Novartis, and Janssen.

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

When I was in Florida a few weeks ago, I met a friend outside who approached me wearing an N-95 mask. He said he was wearing it because the Delta variant was running wild in Florida, and several of his younger unvaccinated employees had contracted it, and he encouraged me to get a COVID booster shot. In the late summer, although the federal government recommended booster shots for anyone 8 months after their original vaccination series, national confusion still reigns, with an Food and Drug Administration advisory panel more recently recommending against a Pfizer booster for all adults, but supporting a booster for those ages 65 and older or at a high risk for severe COVID-19.

At the end of December, I was excited when the local hospital whose staff I am on made the Moderna vaccine available. I had to wait several hours but it was worth it, and I did not care about the low-grade fever and malaise I experienced after the second dose. Astoundingly, I still have patients who have not been vaccinated, although many of them are elderly, frail, or immunocompromised. I think people who publicly argue against vaccination need to visit their local intensive care unit.

While less so than some other physicians, dermatologists are also vulnerable to COVID exposure. You can’t look in someone’s throat, or examine facial skin if they are wearing a mask – and you must lean in to see anything. We take all reasonable precautions, wearing masks, wiping down exam rooms and door handles, keeping the waiting room as empty as possible, using HEPA filters, and keeping exhaust fans going in the rooms continuously. My staff have all been vaccinated (I’m lucky there).

Still, if you are seeing 30 or 40 patients a day of all age groups and working in small unventilated rooms, you could be exposed to the Delta variant. While breakthrough infections among fully vaccinated immunocompetent individuals may be rare, if you do develop a breakthrough case, even if mild or asymptomatic, CDC recommendations include quarantining for at least 10 days. Obviously, this can be disastrous to your practice as a COVID infection works through your office.

This brings us to back to booster shots. Personally, I think all health care workers should be eager to get a booster shot. I also think individuals who have wide public exposure, particularly indoors, such as teachers and retail sales workers, should be eager to get one too. Here are some of the pros, as well as some cons for boosters.
 

Arguments for booster shots

• Booster shots should elevate your antibody levels and make you more resistant to breakthrough infections, but this is still theoretical. Antibody levels decline over time – more rapidly in those over 56 years of age.
• Vaccine doses go to waste every month in the United States, although specific numbers are lacking.
• Vaccinated individuals almost never get hospitalized and die from COVID, presumably even fewer do so after receiving a booster.
• You could unwittingly become a vector. Many of the breakthrough infections are mild and without symptoms. If you do test positive, it could be devastating to your patients, and your medical practice.

Arguments against booster shots

• These vaccine doses should be going to other countries that have low vaccination levels where many of the nasty variants are developing.
• You may have side effects from the vaccine, though thrombosis has only been seen with the Astra-Zeneca and Johnson and Johnson vaccines. Myocarditis is usually seen in younger patients and is almost always self limited.
• Breakthrough infections are rare.

This COVID pandemic is moving and changing so fast, it is bewildering. But with a little luck, COVID could eventually become an annual nuisance like the flu, and the COVID vaccine will become an annual shot based on the newest mutations. For now, my opinion is, get your booster shot.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

When I was in Florida a few weeks ago, I met a friend outside who approached me wearing an N-95 mask. He said he was wearing it because the Delta variant was running wild in Florida, and several of his younger unvaccinated employees had contracted it, and he encouraged me to get a COVID booster shot. In the late summer, although the federal government recommended booster shots for anyone 8 months after their original vaccination series, national confusion still reigns, with an Food and Drug Administration advisory panel more recently recommending against a Pfizer booster for all adults, but supporting a booster for those ages 65 and older or at a high risk for severe COVID-19.

At the end of December, I was excited when the local hospital whose staff I am on made the Moderna vaccine available. I had to wait several hours but it was worth it, and I did not care about the low-grade fever and malaise I experienced after the second dose. Astoundingly, I still have patients who have not been vaccinated, although many of them are elderly, frail, or immunocompromised. I think people who publicly argue against vaccination need to visit their local intensive care unit.

While less so than some other physicians, dermatologists are also vulnerable to COVID exposure. You can’t look in someone’s throat, or examine facial skin if they are wearing a mask – and you must lean in to see anything. We take all reasonable precautions, wearing masks, wiping down exam rooms and door handles, keeping the waiting room as empty as possible, using HEPA filters, and keeping exhaust fans going in the rooms continuously. My staff have all been vaccinated (I’m lucky there).

Still, if you are seeing 30 or 40 patients a day of all age groups and working in small unventilated rooms, you could be exposed to the Delta variant. While breakthrough infections among fully vaccinated immunocompetent individuals may be rare, if you do develop a breakthrough case, even if mild or asymptomatic, CDC recommendations include quarantining for at least 10 days. Obviously, this can be disastrous to your practice as a COVID infection works through your office.

This brings us to back to booster shots. Personally, I think all health care workers should be eager to get a booster shot. I also think individuals who have wide public exposure, particularly indoors, such as teachers and retail sales workers, should be eager to get one too. Here are some of the pros, as well as some cons for boosters.
 

Arguments for booster shots

• Booster shots should elevate your antibody levels and make you more resistant to breakthrough infections, but this is still theoretical. Antibody levels decline over time – more rapidly in those over 56 years of age.
• Vaccine doses go to waste every month in the United States, although specific numbers are lacking.
• Vaccinated individuals almost never get hospitalized and die from COVID, presumably even fewer do so after receiving a booster.
• You could unwittingly become a vector. Many of the breakthrough infections are mild and without symptoms. If you do test positive, it could be devastating to your patients, and your medical practice.

Arguments against booster shots

• These vaccine doses should be going to other countries that have low vaccination levels where many of the nasty variants are developing.
• You may have side effects from the vaccine, though thrombosis has only been seen with the Astra-Zeneca and Johnson and Johnson vaccines. Myocarditis is usually seen in younger patients and is almost always self limited.
• Breakthrough infections are rare.

This COVID pandemic is moving and changing so fast, it is bewildering. But with a little luck, COVID could eventually become an annual nuisance like the flu, and the COVID vaccine will become an annual shot based on the newest mutations. For now, my opinion is, get your booster shot.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

When I was in Florida a few weeks ago, I met a friend outside who approached me wearing an N-95 mask. He said he was wearing it because the Delta variant was running wild in Florida, and several of his younger unvaccinated employees had contracted it, and he encouraged me to get a COVID booster shot. In the late summer, although the federal government recommended booster shots for anyone 8 months after their original vaccination series, national confusion still reigns, with an Food and Drug Administration advisory panel more recently recommending against a Pfizer booster for all adults, but supporting a booster for those ages 65 and older or at a high risk for severe COVID-19.

At the end of December, I was excited when the local hospital whose staff I am on made the Moderna vaccine available. I had to wait several hours but it was worth it, and I did not care about the low-grade fever and malaise I experienced after the second dose. Astoundingly, I still have patients who have not been vaccinated, although many of them are elderly, frail, or immunocompromised. I think people who publicly argue against vaccination need to visit their local intensive care unit.

While less so than some other physicians, dermatologists are also vulnerable to COVID exposure. You can’t look in someone’s throat, or examine facial skin if they are wearing a mask – and you must lean in to see anything. We take all reasonable precautions, wearing masks, wiping down exam rooms and door handles, keeping the waiting room as empty as possible, using HEPA filters, and keeping exhaust fans going in the rooms continuously. My staff have all been vaccinated (I’m lucky there).

Still, if you are seeing 30 or 40 patients a day of all age groups and working in small unventilated rooms, you could be exposed to the Delta variant. While breakthrough infections among fully vaccinated immunocompetent individuals may be rare, if you do develop a breakthrough case, even if mild or asymptomatic, CDC recommendations include quarantining for at least 10 days. Obviously, this can be disastrous to your practice as a COVID infection works through your office.

This brings us to back to booster shots. Personally, I think all health care workers should be eager to get a booster shot. I also think individuals who have wide public exposure, particularly indoors, such as teachers and retail sales workers, should be eager to get one too. Here are some of the pros, as well as some cons for boosters.
 

Arguments for booster shots

• Booster shots should elevate your antibody levels and make you more resistant to breakthrough infections, but this is still theoretical. Antibody levels decline over time – more rapidly in those over 56 years of age.
• Vaccine doses go to waste every month in the United States, although specific numbers are lacking.
• Vaccinated individuals almost never get hospitalized and die from COVID, presumably even fewer do so after receiving a booster.
• You could unwittingly become a vector. Many of the breakthrough infections are mild and without symptoms. If you do test positive, it could be devastating to your patients, and your medical practice.

Arguments against booster shots

• These vaccine doses should be going to other countries that have low vaccination levels where many of the nasty variants are developing.
• You may have side effects from the vaccine, though thrombosis has only been seen with the Astra-Zeneca and Johnson and Johnson vaccines. Myocarditis is usually seen in younger patients and is almost always self limited.
• Breakthrough infections are rare.

This COVID pandemic is moving and changing so fast, it is bewildering. But with a little luck, COVID could eventually become an annual nuisance like the flu, and the COVID vaccine will become an annual shot based on the newest mutations. For now, my opinion is, get your booster shot.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

The Oregon Medical Board has revoked the license of a doctor who didn’t follow COVID-19 guidelines in his office and even told some patients that wearing face masks could lead to carbon-dioxide poisoning.

Steven Arthur LaTulippe’s advice to patients about face masking amounted to “gross negligence” in the practice of medicine and was grounds for discipline, the medical board said in a report.

Mr. LaTulippe, who had a family practice in Dallas, was fined $10,000, Insider reported. The board also said he’d overprescribed opioids for some patients.

The medical board report said Mr. LaTulippe and his wife, who ran the clinic with him, didn’t wear face masks while treating patients from March to December 2020.

Mr. LaTulippe told elderly and pediatric patients that mask wearing could hurt their health by exacerbating COPD and asthma and could contribute to heart attacks and other medical problems, the report said.

“Licensee asserts masks are likely to harm patients by increasing the body’s carbon dioxide content through rebreathing of gas trapped behind a mask,” the report said.

The report noted that “the amount of carbon dioxide rebreathed within a mask is trivial and would easily be expelled by an increase in minute ventilation so small it would not be noticed.”

The report said Mr. LaTulippe told patients they didn’t have to wear a mask in the clinic unless they were “acutely ill,” “coughing,” or “congested,” even though the Centers for Disease Control and Prevention and the Oregon governor had recommended masks be worn to prevent the spread of the virus.

Before coming into the office, patients weren’t asked if they’d had recent contact with anybody who was infected or showed COVID symptoms, the report said.

The medical board first suspended his license in September. He said he would not change his conduct concerning face masks.

“Licensee has confirmed that he will refuse to abide by the state’s COVID-19 protocols in the future as well, affirming that in a choice between losing his medical license versus wearing a mask in his clinic and requiring his patients and staff to wear a mask in his clinic, he will, ‘choose to sacrifice my medical license with no hesitation’ ” the medical board’s report said.

Mr. LaTulippe told the medical board that he was “a strong asset to the public in educating them on the real facts about this pandemic” and that “at least 98% of my patients were so extremely thankful that I did not wear a mask or demand wearing a mask in my clinic.”

The medical board found Mr. LaTulippe engaged in 8 instances of unprofessional or dishonorable conduct, 22 instances of negligence in the practice of medicine, and 5 instances of gross negligence in the practice of medicine.

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

The Oregon Medical Board has revoked the license of a doctor who didn’t follow COVID-19 guidelines in his office and even told some patients that wearing face masks could lead to carbon-dioxide poisoning.

Steven Arthur LaTulippe’s advice to patients about face masking amounted to “gross negligence” in the practice of medicine and was grounds for discipline, the medical board said in a report.

Mr. LaTulippe, who had a family practice in Dallas, was fined $10,000, Insider reported. The board also said he’d overprescribed opioids for some patients.

The medical board report said Mr. LaTulippe and his wife, who ran the clinic with him, didn’t wear face masks while treating patients from March to December 2020.

Mr. LaTulippe told elderly and pediatric patients that mask wearing could hurt their health by exacerbating COPD and asthma and could contribute to heart attacks and other medical problems, the report said.

“Licensee asserts masks are likely to harm patients by increasing the body’s carbon dioxide content through rebreathing of gas trapped behind a mask,” the report said.

The report noted that “the amount of carbon dioxide rebreathed within a mask is trivial and would easily be expelled by an increase in minute ventilation so small it would not be noticed.”

The report said Mr. LaTulippe told patients they didn’t have to wear a mask in the clinic unless they were “acutely ill,” “coughing,” or “congested,” even though the Centers for Disease Control and Prevention and the Oregon governor had recommended masks be worn to prevent the spread of the virus.

Before coming into the office, patients weren’t asked if they’d had recent contact with anybody who was infected or showed COVID symptoms, the report said.

The medical board first suspended his license in September. He said he would not change his conduct concerning face masks.

“Licensee has confirmed that he will refuse to abide by the state’s COVID-19 protocols in the future as well, affirming that in a choice between losing his medical license versus wearing a mask in his clinic and requiring his patients and staff to wear a mask in his clinic, he will, ‘choose to sacrifice my medical license with no hesitation’ ” the medical board’s report said.

Mr. LaTulippe told the medical board that he was “a strong asset to the public in educating them on the real facts about this pandemic” and that “at least 98% of my patients were so extremely thankful that I did not wear a mask or demand wearing a mask in my clinic.”

The medical board found Mr. LaTulippe engaged in 8 instances of unprofessional or dishonorable conduct, 22 instances of negligence in the practice of medicine, and 5 instances of gross negligence in the practice of medicine.

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

The Oregon Medical Board has revoked the license of a doctor who didn’t follow COVID-19 guidelines in his office and even told some patients that wearing face masks could lead to carbon-dioxide poisoning.

Steven Arthur LaTulippe’s advice to patients about face masking amounted to “gross negligence” in the practice of medicine and was grounds for discipline, the medical board said in a report.

Mr. LaTulippe, who had a family practice in Dallas, was fined $10,000, Insider reported. The board also said he’d overprescribed opioids for some patients.

The medical board report said Mr. LaTulippe and his wife, who ran the clinic with him, didn’t wear face masks while treating patients from March to December 2020.

Mr. LaTulippe told elderly and pediatric patients that mask wearing could hurt their health by exacerbating COPD and asthma and could contribute to heart attacks and other medical problems, the report said.

“Licensee asserts masks are likely to harm patients by increasing the body’s carbon dioxide content through rebreathing of gas trapped behind a mask,” the report said.

The report noted that “the amount of carbon dioxide rebreathed within a mask is trivial and would easily be expelled by an increase in minute ventilation so small it would not be noticed.”

The report said Mr. LaTulippe told patients they didn’t have to wear a mask in the clinic unless they were “acutely ill,” “coughing,” or “congested,” even though the Centers for Disease Control and Prevention and the Oregon governor had recommended masks be worn to prevent the spread of the virus.

Before coming into the office, patients weren’t asked if they’d had recent contact with anybody who was infected or showed COVID symptoms, the report said.

The medical board first suspended his license in September. He said he would not change his conduct concerning face masks.

“Licensee has confirmed that he will refuse to abide by the state’s COVID-19 protocols in the future as well, affirming that in a choice between losing his medical license versus wearing a mask in his clinic and requiring his patients and staff to wear a mask in his clinic, he will, ‘choose to sacrifice my medical license with no hesitation’ ” the medical board’s report said.

Mr. LaTulippe told the medical board that he was “a strong asset to the public in educating them on the real facts about this pandemic” and that “at least 98% of my patients were so extremely thankful that I did not wear a mask or demand wearing a mask in my clinic.”

The medical board found Mr. LaTulippe engaged in 8 instances of unprofessional or dishonorable conduct, 22 instances of negligence in the practice of medicine, and 5 instances of gross negligence in the practice of medicine.

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

A 26-year-old woman who reports a history of acyclovir-resistant herpes complains of a recurring, stinging rash around her mouth. Topical tacrolimus made it worse, she said. On exam, she has somewhat grouped pustules on her cutaneous lip. I mentioned her to colleagues, saying: “I’ve a patient with acyclovir-resistant herpes who isn’t improving on high-dose Valtrex.” They proffered a few alternative diagnoses and treatment recommendations. I tried several to no avail.

This case illustrates a common problem in medicine: Noise, the chance variability in judgments that should all be identical (it is after all only one condition). Nobel Prize–winning economist Daniel Kahneman, PhD, with two other authors, has written a brilliant book about this cognitive unreliability called “Noise: A Flaw in Human Judgment” (New York: Hachette Book Group, 2021).

Both bias and noise create trouble for us. Although biases get more attention, noise is both more prevalent and insidious. In a 2016 article, Dr. Kahneman and coauthors use a bathroom scale as an analogy to explain the difference. “We would say that the scale is biased if its readings are generally either too high or too low. A scale that consistently underestimates true weight by exactly 4 pounds is seriously biased but free of noise. A scale that gives two different readings when you step on it twice is noisy.” In the case presented, “measurements” by me and my colleagues were returning different “readings.” There is one true diagnosis and best treatment, yet because of noise, we waste time and resources by not getting it right the first time.

There is also evidence of bias in this case. For example, there’s probably some confirmation bias: The patient said she has a history of antiviral-resistant herpes; therefore, her rash might appear to be herpes. Also there might be salience bias: it’s easy to see how prominent pustules might be herpes simplex virus. Noise is an issue in many misdiagnoses, but trickier to see. In most instances, we don’t have the opportunity to get multiple assessments of the same case. When examined though, interrater reliability in medicine is often found to be shockingly low, an indication of how much noise there is in our clinical judgments. This leads to waste, frustration – and can even be dangerous when we’re trying to diagnose cancers such as melanoma, lung, or breast cancer.

Dr. Kahneman and colleagues have excellent recommendations on how to reduce noise, such as tips for good decision hygiene (e.g., using differential diagnoses) and using algorithms (e.g., calculating Apgar or LACE scores). I also liked their strategy of aggregating expert opinions. Fascinatingly, averaging multiple independent assessments is mathematically guaranteed to reduce noise. (God, I love economists). This is true of measurements and opinions: If you use 100 judgments for a case, you reduce noise by 90% (the noise is divided by the square root of the number of judgments averaged). So 20 colleagues’ opinions would reduce noise by almost 80%. However, those 20 opinions must be independent to avoid spurious agreement. (Again, math for the win.)

I showed photos of my patient to a few other dermatologists. They independently returned the same result: perioral dermatitis. This was the correct diagnosis and reminded me why grand rounds and tumor boards are such a great help. Multiple, independent assessments are more likely to get it right than just one opinion because we are canceling out the noise. But remember, grand rounds has to be old-school style – no looking at your coresident answers before giving yours!

Our patient cleared after restarting her topical tacrolimus and a bit of doxycycline. Credit the wisdom of the crowd. Reassuringly though, Dr. Kahneman also shows that expertise does matter in minimizing error. So that fellowship you did was still a great idea.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. He reports having no conflicts of interest. Write to him at [email protected].

A 26-year-old woman who reports a history of acyclovir-resistant herpes complains of a recurring, stinging rash around her mouth. Topical tacrolimus made it worse, she said. On exam, she has somewhat grouped pustules on her cutaneous lip. I mentioned her to colleagues, saying: “I’ve a patient with acyclovir-resistant herpes who isn’t improving on high-dose Valtrex.” They proffered a few alternative diagnoses and treatment recommendations. I tried several to no avail.

This case illustrates a common problem in medicine: Noise, the chance variability in judgments that should all be identical (it is after all only one condition). Nobel Prize–winning economist Daniel Kahneman, PhD, with two other authors, has written a brilliant book about this cognitive unreliability called “Noise: A Flaw in Human Judgment” (New York: Hachette Book Group, 2021).

Both bias and noise create trouble for us. Although biases get more attention, noise is both more prevalent and insidious. In a 2016 article, Dr. Kahneman and coauthors use a bathroom scale as an analogy to explain the difference. “We would say that the scale is biased if its readings are generally either too high or too low. A scale that consistently underestimates true weight by exactly 4 pounds is seriously biased but free of noise. A scale that gives two different readings when you step on it twice is noisy.” In the case presented, “measurements” by me and my colleagues were returning different “readings.” There is one true diagnosis and best treatment, yet because of noise, we waste time and resources by not getting it right the first time.

There is also evidence of bias in this case. For example, there’s probably some confirmation bias: The patient said she has a history of antiviral-resistant herpes; therefore, her rash might appear to be herpes. Also there might be salience bias: it’s easy to see how prominent pustules might be herpes simplex virus. Noise is an issue in many misdiagnoses, but trickier to see. In most instances, we don’t have the opportunity to get multiple assessments of the same case. When examined though, interrater reliability in medicine is often found to be shockingly low, an indication of how much noise there is in our clinical judgments. This leads to waste, frustration – and can even be dangerous when we’re trying to diagnose cancers such as melanoma, lung, or breast cancer.

Dr. Kahneman and colleagues have excellent recommendations on how to reduce noise, such as tips for good decision hygiene (e.g., using differential diagnoses) and using algorithms (e.g., calculating Apgar or LACE scores). I also liked their strategy of aggregating expert opinions. Fascinatingly, averaging multiple independent assessments is mathematically guaranteed to reduce noise. (God, I love economists). This is true of measurements and opinions: If you use 100 judgments for a case, you reduce noise by 90% (the noise is divided by the square root of the number of judgments averaged). So 20 colleagues’ opinions would reduce noise by almost 80%. However, those 20 opinions must be independent to avoid spurious agreement. (Again, math for the win.)

I showed photos of my patient to a few other dermatologists. They independently returned the same result: perioral dermatitis. This was the correct diagnosis and reminded me why grand rounds and tumor boards are such a great help. Multiple, independent assessments are more likely to get it right than just one opinion because we are canceling out the noise. But remember, grand rounds has to be old-school style – no looking at your coresident answers before giving yours!

Our patient cleared after restarting her topical tacrolimus and a bit of doxycycline. Credit the wisdom of the crowd. Reassuringly though, Dr. Kahneman also shows that expertise does matter in minimizing error. So that fellowship you did was still a great idea.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. He reports having no conflicts of interest. Write to him at [email protected].

A 26-year-old woman who reports a history of acyclovir-resistant herpes complains of a recurring, stinging rash around her mouth. Topical tacrolimus made it worse, she said. On exam, she has somewhat grouped pustules on her cutaneous lip. I mentioned her to colleagues, saying: “I’ve a patient with acyclovir-resistant herpes who isn’t improving on high-dose Valtrex.” They proffered a few alternative diagnoses and treatment recommendations. I tried several to no avail.

This case illustrates a common problem in medicine: Noise, the chance variability in judgments that should all be identical (it is after all only one condition). Nobel Prize–winning economist Daniel Kahneman, PhD, with two other authors, has written a brilliant book about this cognitive unreliability called “Noise: A Flaw in Human Judgment” (New York: Hachette Book Group, 2021).

Both bias and noise create trouble for us. Although biases get more attention, noise is both more prevalent and insidious. In a 2016 article, Dr. Kahneman and coauthors use a bathroom scale as an analogy to explain the difference. “We would say that the scale is biased if its readings are generally either too high or too low. A scale that consistently underestimates true weight by exactly 4 pounds is seriously biased but free of noise. A scale that gives two different readings when you step on it twice is noisy.” In the case presented, “measurements” by me and my colleagues were returning different “readings.” There is one true diagnosis and best treatment, yet because of noise, we waste time and resources by not getting it right the first time.

There is also evidence of bias in this case. For example, there’s probably some confirmation bias: The patient said she has a history of antiviral-resistant herpes; therefore, her rash might appear to be herpes. Also there might be salience bias: it’s easy to see how prominent pustules might be herpes simplex virus. Noise is an issue in many misdiagnoses, but trickier to see. In most instances, we don’t have the opportunity to get multiple assessments of the same case. When examined though, interrater reliability in medicine is often found to be shockingly low, an indication of how much noise there is in our clinical judgments. This leads to waste, frustration – and can even be dangerous when we’re trying to diagnose cancers such as melanoma, lung, or breast cancer.

Dr. Kahneman and colleagues have excellent recommendations on how to reduce noise, such as tips for good decision hygiene (e.g., using differential diagnoses) and using algorithms (e.g., calculating Apgar or LACE scores). I also liked their strategy of aggregating expert opinions. Fascinatingly, averaging multiple independent assessments is mathematically guaranteed to reduce noise. (God, I love economists). This is true of measurements and opinions: If you use 100 judgments for a case, you reduce noise by 90% (the noise is divided by the square root of the number of judgments averaged). So 20 colleagues’ opinions would reduce noise by almost 80%. However, those 20 opinions must be independent to avoid spurious agreement. (Again, math for the win.)

I showed photos of my patient to a few other dermatologists. They independently returned the same result: perioral dermatitis. This was the correct diagnosis and reminded me why grand rounds and tumor boards are such a great help. Multiple, independent assessments are more likely to get it right than just one opinion because we are canceling out the noise. But remember, grand rounds has to be old-school style – no looking at your coresident answers before giving yours!

Our patient cleared after restarting her topical tacrolimus and a bit of doxycycline. Credit the wisdom of the crowd. Reassuringly though, Dr. Kahneman also shows that expertise does matter in minimizing error. So that fellowship you did was still a great idea.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. He reports having no conflicts of interest. Write to him at [email protected].

To the Editor:

A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.

Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.

A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.

The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.

Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.¹ Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.² Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.³ Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.^3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.⁵ An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.⁶ Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.²

Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.⁷ Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.^7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.⁹ Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4⁺ and CD8⁺ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.⁷ In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.¹⁰ This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.

We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.

To the Editor:

A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.

Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.

A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.

The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.

Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.¹ Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.² Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.³ Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.^3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.⁵ An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.⁶ Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.²

Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.⁷ Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.^7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.⁹ Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4⁺ and CD8⁺ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.⁷ In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.¹⁰ This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.

We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.

To the Editor:

A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.

Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.

A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.

The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.

Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.¹ Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.² Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.³ Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.^3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.⁵ An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.⁶ Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.²

Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.⁷ Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.^7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.⁹ Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4⁺ and CD8⁺ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.⁷ In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.¹⁰ This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.

We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.

The Food and Drug Administration today gave the nod to topical ruxolitinib cream for the treatment of non-immunocompromised patients with mild to moderate atopic dermatitis ages 12 years and older, making it the first topical JAK inhibitor approved for AD – and the first JAK inhibitor approved for this indication – in the United States.

The approval is limited to patients whose AD is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

“Approval of topical ruxolitinib fills a major gap in the treatment of atopic dermatitis: a safe, effective, and tolerable non-steroidal topical therapy,” Eric L. Simpson, MD, professor of dermatology and director of the Oregon Health & Science University Dermatology Clinical Research Center, Portland, told this news organization. “This approval will allow for long-term treatment without the concern of steroid side effects. From earlier studies, ruxolitinib cream appears to be as effective as a medium-potency topical steroid. These efficacy levels and low incidence of burning will be a welcome addition to our current nonsteroidal therapies.”

The drug’s approval was based on results from two phase 3, randomized studies of identical design involving 1,249 patients aged 12 years and older with AD: TRuE-AD1 and TRuE-AD2. In these studies, ruxolitinib cream demonstrated anti-inflammatory activity, with rapid and sustained antipruritic action, compared with vehicle. In the trials, patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 and 3%-20% of affected body surface area (BSA) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 continuous weeks. The 1.5% concentration was approved by the FDA.

A study first published in May of 2021 found that significantly more patients in TRuE-AD1 and TRuE-AD2 achieved IGA treatment success with 0.75% (50% vs. 39%, respectively) and 1.5% ruxolitinib cream (53.8% vs. 51.3%), compared with vehicle (15.1% vs. 7.6%; P < .0001) at week 8. In addition, significant reductions in itch, compared with vehicle, were reported within 12 hours of first applying 1.5% ruxolitinib cream (P < .05).

More key findings from TRuE-AD1 and TRuE-AD2 are scheduled to be presented during the upcoming European Academy of Dermatology and Venereology meeting Sept. 29-Oct. 2, but during the Revolutionizing Atopic Dermatitis Symposium on June 13, Kim Papp, MD, PhD, presented long-term safety data of ruxolitinib cream in patients who were followed for an additional 44 weeks. Dr. Papp, a dermatologist and founder of Probity Medical Research, Waterloo, Ont., reported that 543 patients from TRuE-AD1 and 530 from TRuE-AD2 entered the long-term analysis and that about 78% of these patients completed the study. From weeks 12 to 52, the proportion of patients with an IGA score of 0 or 1 with 0.75% and 1.5% ruxolitinib cream ranged from 62%-77% and 67%-77%, respectively, in TRuE-AD1, to 60%-77% and 72%-80% in TRuE-AD2.

The measured mean total affected BSA was less than 3% throughout the follow-up period in the 1.5% ruxolitinib cream arm in TRuE-AD1 and TRuE-AD2 and was less than 3% in the 0.75% ruxolitinib cream arm during most of the study period.

In a pooled safety analysis, treatment-emergent adverse events (TEAEs) were reported in 60% and 54% of patients who applied 0.75% and 1.5% ruxolitinib cream, respectively, over 44 weeks. The frequency of application-site reactions remained low. Specifically, treatment-related adverse events were reported in 5% of patients who applied 0.75% ruxolitinib cream and in 3% of patients who applied 1.5% ruxolitinib cream; none were serious. TEAEs led to discontinuation in 2% of patients in the 0.75% ruxolitinib cream group, and no patients in the 1.5% ruxolitinib cream group.

Dr. Papp and his colleagues observed that the most common treatment adverse events were upper respiratory tract infections and nasopharyngitis. According to Incyte’s press release, the most common treatment-emergent adverse reactions in patients treated with ruxolitinib during clinical trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increases, urticaria, folliculitis, tonsillitis, and rhinorrhea. The labeling includes boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, seen with oral JAK inhibitors for inflammatory conditions.

Incyte will market ruxolitinib under the trade name Opzelura.

Dr. Simpson disclosed that he is a consultant to and/or an investigator for several pharmaceutical companies, including Incyte, Regeneron/Sanofi, Eli Lilly and Company, AbbVie, and Pfizer.

Dr. Papp disclosed that he has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for several pharmaceutical companies, including Incyte.

Commentary by Robert Sidbury, MD, MPH

Another nonsteroidal topical medication approved for atopic dermatitis (AD)? Thank goodness. Topical ruxolitinib 1.5% cream twice daily for mild to moderate AD demonstrated excellent efficacy vs. placebo in duplicative trials (53.8/51.3% vs. 15.1%/7.6%; P < .001), with a reassuring safety profile. Application site reactions were uncommon, though past experience with other new nonsteroidal agents suggests judgment be reserved on that score. More compelling was the fact that no patients discontinued therapy in the 1.5% arm, and adverse events were mild and self-limited such as nasopharyngitis and diarrhea. This stands in contradistinction to the boxed warning attached to JAK inhibitors (topical and systemic) against a daunting list of destructive possibilities: malignancy, infection, cardiovascular disease, and blood clots. None of these things was seen in these topical ruxolitinib trials.

Dr. Sidbury is chief of dermatology at Seattle Children's Hospital and professor, department of pediatrics, University of Washington, Seattle. He is a site principal investigator for dupilumab trials, for which the hospital has a contract with Regeneron.

This article was updated 6/16/22.

The Food and Drug Administration today gave the nod to topical ruxolitinib cream for the treatment of non-immunocompromised patients with mild to moderate atopic dermatitis ages 12 years and older, making it the first topical JAK inhibitor approved for AD – and the first JAK inhibitor approved for this indication – in the United States.

The approval is limited to patients whose AD is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

“Approval of topical ruxolitinib fills a major gap in the treatment of atopic dermatitis: a safe, effective, and tolerable non-steroidal topical therapy,” Eric L. Simpson, MD, professor of dermatology and director of the Oregon Health & Science University Dermatology Clinical Research Center, Portland, told this news organization. “This approval will allow for long-term treatment without the concern of steroid side effects. From earlier studies, ruxolitinib cream appears to be as effective as a medium-potency topical steroid. These efficacy levels and low incidence of burning will be a welcome addition to our current nonsteroidal therapies.”

The drug’s approval was based on results from two phase 3, randomized studies of identical design involving 1,249 patients aged 12 years and older with AD: TRuE-AD1 and TRuE-AD2. In these studies, ruxolitinib cream demonstrated anti-inflammatory activity, with rapid and sustained antipruritic action, compared with vehicle. In the trials, patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 and 3%-20% of affected body surface area (BSA) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 continuous weeks. The 1.5% concentration was approved by the FDA.

A study first published in May of 2021 found that significantly more patients in TRuE-AD1 and TRuE-AD2 achieved IGA treatment success with 0.75% (50% vs. 39%, respectively) and 1.5% ruxolitinib cream (53.8% vs. 51.3%), compared with vehicle (15.1% vs. 7.6%; P < .0001) at week 8. In addition, significant reductions in itch, compared with vehicle, were reported within 12 hours of first applying 1.5% ruxolitinib cream (P < .05).

More key findings from TRuE-AD1 and TRuE-AD2 are scheduled to be presented during the upcoming European Academy of Dermatology and Venereology meeting Sept. 29-Oct. 2, but during the Revolutionizing Atopic Dermatitis Symposium on June 13, Kim Papp, MD, PhD, presented long-term safety data of ruxolitinib cream in patients who were followed for an additional 44 weeks. Dr. Papp, a dermatologist and founder of Probity Medical Research, Waterloo, Ont., reported that 543 patients from TRuE-AD1 and 530 from TRuE-AD2 entered the long-term analysis and that about 78% of these patients completed the study. From weeks 12 to 52, the proportion of patients with an IGA score of 0 or 1 with 0.75% and 1.5% ruxolitinib cream ranged from 62%-77% and 67%-77%, respectively, in TRuE-AD1, to 60%-77% and 72%-80% in TRuE-AD2.

The measured mean total affected BSA was less than 3% throughout the follow-up period in the 1.5% ruxolitinib cream arm in TRuE-AD1 and TRuE-AD2 and was less than 3% in the 0.75% ruxolitinib cream arm during most of the study period.

In a pooled safety analysis, treatment-emergent adverse events (TEAEs) were reported in 60% and 54% of patients who applied 0.75% and 1.5% ruxolitinib cream, respectively, over 44 weeks. The frequency of application-site reactions remained low. Specifically, treatment-related adverse events were reported in 5% of patients who applied 0.75% ruxolitinib cream and in 3% of patients who applied 1.5% ruxolitinib cream; none were serious. TEAEs led to discontinuation in 2% of patients in the 0.75% ruxolitinib cream group, and no patients in the 1.5% ruxolitinib cream group.

Dr. Papp and his colleagues observed that the most common treatment adverse events were upper respiratory tract infections and nasopharyngitis. According to Incyte’s press release, the most common treatment-emergent adverse reactions in patients treated with ruxolitinib during clinical trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increases, urticaria, folliculitis, tonsillitis, and rhinorrhea. The labeling includes boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, seen with oral JAK inhibitors for inflammatory conditions.

Incyte will market ruxolitinib under the trade name Opzelura.

Dr. Simpson disclosed that he is a consultant to and/or an investigator for several pharmaceutical companies, including Incyte, Regeneron/Sanofi, Eli Lilly and Company, AbbVie, and Pfizer.

Dr. Papp disclosed that he has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for several pharmaceutical companies, including Incyte.

Commentary by Robert Sidbury, MD, MPH

Another nonsteroidal topical medication approved for atopic dermatitis (AD)? Thank goodness. Topical ruxolitinib 1.5% cream twice daily for mild to moderate AD demonstrated excellent efficacy vs. placebo in duplicative trials (53.8/51.3% vs. 15.1%/7.6%; P < .001), with a reassuring safety profile. Application site reactions were uncommon, though past experience with other new nonsteroidal agents suggests judgment be reserved on that score. More compelling was the fact that no patients discontinued therapy in the 1.5% arm, and adverse events were mild and self-limited such as nasopharyngitis and diarrhea. This stands in contradistinction to the boxed warning attached to JAK inhibitors (topical and systemic) against a daunting list of destructive possibilities: malignancy, infection, cardiovascular disease, and blood clots. None of these things was seen in these topical ruxolitinib trials.

Dr. Sidbury is chief of dermatology at Seattle Children's Hospital and professor, department of pediatrics, University of Washington, Seattle. He is a site principal investigator for dupilumab trials, for which the hospital has a contract with Regeneron.

This article was updated 6/16/22.

The Food and Drug Administration today gave the nod to topical ruxolitinib cream for the treatment of non-immunocompromised patients with mild to moderate atopic dermatitis ages 12 years and older, making it the first topical JAK inhibitor approved for AD – and the first JAK inhibitor approved for this indication – in the United States.

The approval is limited to patients whose AD is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

“Approval of topical ruxolitinib fills a major gap in the treatment of atopic dermatitis: a safe, effective, and tolerable non-steroidal topical therapy,” Eric L. Simpson, MD, professor of dermatology and director of the Oregon Health & Science University Dermatology Clinical Research Center, Portland, told this news organization. “This approval will allow for long-term treatment without the concern of steroid side effects. From earlier studies, ruxolitinib cream appears to be as effective as a medium-potency topical steroid. These efficacy levels and low incidence of burning will be a welcome addition to our current nonsteroidal therapies.”

The drug’s approval was based on results from two phase 3, randomized studies of identical design involving 1,249 patients aged 12 years and older with AD: TRuE-AD1 and TRuE-AD2. In these studies, ruxolitinib cream demonstrated anti-inflammatory activity, with rapid and sustained antipruritic action, compared with vehicle. In the trials, patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 and 3%-20% of affected body surface area (BSA) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 continuous weeks. The 1.5% concentration was approved by the FDA.

A study first published in May of 2021 found that significantly more patients in TRuE-AD1 and TRuE-AD2 achieved IGA treatment success with 0.75% (50% vs. 39%, respectively) and 1.5% ruxolitinib cream (53.8% vs. 51.3%), compared with vehicle (15.1% vs. 7.6%; P < .0001) at week 8. In addition, significant reductions in itch, compared with vehicle, were reported within 12 hours of first applying 1.5% ruxolitinib cream (P < .05).

More key findings from TRuE-AD1 and TRuE-AD2 are scheduled to be presented during the upcoming European Academy of Dermatology and Venereology meeting Sept. 29-Oct. 2, but during the Revolutionizing Atopic Dermatitis Symposium on June 13, Kim Papp, MD, PhD, presented long-term safety data of ruxolitinib cream in patients who were followed for an additional 44 weeks. Dr. Papp, a dermatologist and founder of Probity Medical Research, Waterloo, Ont., reported that 543 patients from TRuE-AD1 and 530 from TRuE-AD2 entered the long-term analysis and that about 78% of these patients completed the study. From weeks 12 to 52, the proportion of patients with an IGA score of 0 or 1 with 0.75% and 1.5% ruxolitinib cream ranged from 62%-77% and 67%-77%, respectively, in TRuE-AD1, to 60%-77% and 72%-80% in TRuE-AD2.

The measured mean total affected BSA was less than 3% throughout the follow-up period in the 1.5% ruxolitinib cream arm in TRuE-AD1 and TRuE-AD2 and was less than 3% in the 0.75% ruxolitinib cream arm during most of the study period.

In a pooled safety analysis, treatment-emergent adverse events (TEAEs) were reported in 60% and 54% of patients who applied 0.75% and 1.5% ruxolitinib cream, respectively, over 44 weeks. The frequency of application-site reactions remained low. Specifically, treatment-related adverse events were reported in 5% of patients who applied 0.75% ruxolitinib cream and in 3% of patients who applied 1.5% ruxolitinib cream; none were serious. TEAEs led to discontinuation in 2% of patients in the 0.75% ruxolitinib cream group, and no patients in the 1.5% ruxolitinib cream group.

Dr. Papp and his colleagues observed that the most common treatment adverse events were upper respiratory tract infections and nasopharyngitis. According to Incyte’s press release, the most common treatment-emergent adverse reactions in patients treated with ruxolitinib during clinical trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increases, urticaria, folliculitis, tonsillitis, and rhinorrhea. The labeling includes boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, seen with oral JAK inhibitors for inflammatory conditions.

Incyte will market ruxolitinib under the trade name Opzelura.

Dr. Simpson disclosed that he is a consultant to and/or an investigator for several pharmaceutical companies, including Incyte, Regeneron/Sanofi, Eli Lilly and Company, AbbVie, and Pfizer.

Dr. Papp disclosed that he has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for several pharmaceutical companies, including Incyte.

Commentary by Robert Sidbury, MD, MPH

Another nonsteroidal topical medication approved for atopic dermatitis (AD)? Thank goodness. Topical ruxolitinib 1.5% cream twice daily for mild to moderate AD demonstrated excellent efficacy vs. placebo in duplicative trials (53.8/51.3% vs. 15.1%/7.6%; P < .001), with a reassuring safety profile. Application site reactions were uncommon, though past experience with other new nonsteroidal agents suggests judgment be reserved on that score. More compelling was the fact that no patients discontinued therapy in the 1.5% arm, and adverse events were mild and self-limited such as nasopharyngitis and diarrhea. This stands in contradistinction to the boxed warning attached to JAK inhibitors (topical and systemic) against a daunting list of destructive possibilities: malignancy, infection, cardiovascular disease, and blood clots. None of these things was seen in these topical ruxolitinib trials.

Dr. Sidbury is chief of dermatology at Seattle Children's Hospital and professor, department of pediatrics, University of Washington, Seattle. He is a site principal investigator for dupilumab trials, for which the hospital has a contract with Regeneron.

This article was updated 6/16/22.

To the Editor:

PTEN hamartoma tumor syndrome (PHTS) encompasses a spectrum of disorders that most commonly are caused by autosomal-dominant germline mutations in the phosphatase and tensin homolog, PTEN, tumor suppressor gene on chromosome 10q23. We describe a patient who presented with clinical features of PHTS and Birt-Hogg-Dubé syndrome (BHDS). Because the genetic mutations associated with both PHTS and BHDS result in altered mammalian target of rapamycin (mTOR) signaling, patients may have overlapping phenotypic features.

A 51-year-old man with a history of multiple carcinomas presented for evaluation of flesh-colored papules on the cheeks, nose, tongue, and hands, in addition to numerous skin tags on the neck, axillae, and lower abdomen bilaterally. His medical history was notable for several nasal and gastrointestinal tract polyps, chromophobe renal cell carcinoma, cutaneous lipomas, atypical carcinoid syndrome of the right lung, and a multinodular thyroid. His family history was notable for small cell lung cancer in his father, breast cancer and pancreatic cancer in his maternal aunt, esophageal cancer in his maternal grandfather, and celiac disease in his daughter.

Clinical examination revealed flesh-colored, dome-shaped papules measuring 1 to 2 mm in diameter on the nose and cheeks (Figure 1). He had hyperkeratotic papules on the dorsal fingers, consistent with acral keratoses. Additionally, multiple flesh-colored papules with a cobblestonelike appearance were noted on the oral mucosa (Figure 2). Other findings included pedunculated papules on the neck, axillae, and lower abdomen bilaterally, consistent with fibroepithelial polyps, as well as hyperpigmented velvety plaques on the axillae, characteristic of acanthosis nigricans (Figure 3). A shave biopsy of a papule on the right cheek revealed a proliferation of plump stellate fibroblasts, small blood vessels, and thick collagen bundles, characteristic of a fibrous papule (Figure 4).

Differential diagnoses for our patient included BHDS and Cowden syndrome (CS). Due to the combination of extensive family history of multiorgan cancers as well as the clinical findings, he was referred to a geneticist for further evaluation. Genetic analysis was positive for a heterozygous mutation variant of uncertain significance in the PTEN gene.

The PHTS disorders include CS, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, and Proteus-like syndrome (Table).^1-9 Our patient’s clinical findings were indicative of CS, a rare genodermatosis characterized by multiple hamartomas and neoplasms of ectodermal, mesodermal, and endodermal origin.¹ Most CS patients develop trichilemmomas of the central face, mucocutaneous papillomatous papules, and acral and plantar keratoses by the third decade of life.¹ Importantly, CS patients have an increased risk for breast, thyroid, renal, endometrial, and colorectal cancers, as well as melanoma, with estimated lifetime risks of 85%, 35%, 33%, 28%, 9%, and 6%, respectively.^2,10

Regarding the pathophysiology of PHTS disorders, PTEN encodes a phosphatase that inhibits phosphoinositide 3-kinase/Akt and mTOR signaling pathways, thereby controlling cell proliferation, cell-cycle progression, and apoptosis.^2,3 Loss of PTEN function, as seen in CS patients, results in an increased risk for cancer.² Other genetic diseases, including juvenile polyposis syndrome, Proteus syndrome, tuberous sclerosis, and Peutz-Jeghers syndrome, have phenotypic similarities to PHTS.³ Specifically, loss-of-function mutations of TSC1 and TSC2, tumor suppressor genes associated with tuberous sclerosis, similarly result in dysregulation of mTOR signaling.

Our patient also had some clinical features characteristic of BHDS, such as flesh-colored facial papules, acrochordonlike lesions, and chromophobe renal cell carcinoma.¹¹ Birt-Hogg-Dubé syndrome most often is caused by an autosomal-dominant germline mutation in FLCN, a tumor suppressor gene.¹¹ Interestingly, FLCN interacts with AMP-activated protein kinase to help regulate mTOR signaling, which may explain phenotypic similarities seen in CS and BHDS.¹²

Because the PHTS disorders and BHDS result in similar functional consequences on the mTOR signaling pathway, patients can present with overlapping clinical features that may be diagnostically challenging. Management includes patient education regarding cancer risk, surveillance for early detection of malignancy, and genetic counseling for family members.² It is important for clinicians to appreciate phenotypic similarities between PHTS and other disorders affecting mTOR signaling to prevent delays in diagnosis.

To the Editor:

PTEN hamartoma tumor syndrome (PHTS) encompasses a spectrum of disorders that most commonly are caused by autosomal-dominant germline mutations in the phosphatase and tensin homolog, PTEN, tumor suppressor gene on chromosome 10q23. We describe a patient who presented with clinical features of PHTS and Birt-Hogg-Dubé syndrome (BHDS). Because the genetic mutations associated with both PHTS and BHDS result in altered mammalian target of rapamycin (mTOR) signaling, patients may have overlapping phenotypic features.

A 51-year-old man with a history of multiple carcinomas presented for evaluation of flesh-colored papules on the cheeks, nose, tongue, and hands, in addition to numerous skin tags on the neck, axillae, and lower abdomen bilaterally. His medical history was notable for several nasal and gastrointestinal tract polyps, chromophobe renal cell carcinoma, cutaneous lipomas, atypical carcinoid syndrome of the right lung, and a multinodular thyroid. His family history was notable for small cell lung cancer in his father, breast cancer and pancreatic cancer in his maternal aunt, esophageal cancer in his maternal grandfather, and celiac disease in his daughter.

Clinical examination revealed flesh-colored, dome-shaped papules measuring 1 to 2 mm in diameter on the nose and cheeks (Figure 1). He had hyperkeratotic papules on the dorsal fingers, consistent with acral keratoses. Additionally, multiple flesh-colored papules with a cobblestonelike appearance were noted on the oral mucosa (Figure 2). Other findings included pedunculated papules on the neck, axillae, and lower abdomen bilaterally, consistent with fibroepithelial polyps, as well as hyperpigmented velvety plaques on the axillae, characteristic of acanthosis nigricans (Figure 3). A shave biopsy of a papule on the right cheek revealed a proliferation of plump stellate fibroblasts, small blood vessels, and thick collagen bundles, characteristic of a fibrous papule (Figure 4).

Differential diagnoses for our patient included BHDS and Cowden syndrome (CS). Due to the combination of extensive family history of multiorgan cancers as well as the clinical findings, he was referred to a geneticist for further evaluation. Genetic analysis was positive for a heterozygous mutation variant of uncertain significance in the PTEN gene.

The PHTS disorders include CS, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, and Proteus-like syndrome (Table).^1-9 Our patient’s clinical findings were indicative of CS, a rare genodermatosis characterized by multiple hamartomas and neoplasms of ectodermal, mesodermal, and endodermal origin.¹ Most CS patients develop trichilemmomas of the central face, mucocutaneous papillomatous papules, and acral and plantar keratoses by the third decade of life.¹ Importantly, CS patients have an increased risk for breast, thyroid, renal, endometrial, and colorectal cancers, as well as melanoma, with estimated lifetime risks of 85%, 35%, 33%, 28%, 9%, and 6%, respectively.^2,10

Regarding the pathophysiology of PHTS disorders, PTEN encodes a phosphatase that inhibits phosphoinositide 3-kinase/Akt and mTOR signaling pathways, thereby controlling cell proliferation, cell-cycle progression, and apoptosis.^2,3 Loss of PTEN function, as seen in CS patients, results in an increased risk for cancer.² Other genetic diseases, including juvenile polyposis syndrome, Proteus syndrome, tuberous sclerosis, and Peutz-Jeghers syndrome, have phenotypic similarities to PHTS.³ Specifically, loss-of-function mutations of TSC1 and TSC2, tumor suppressor genes associated with tuberous sclerosis, similarly result in dysregulation of mTOR signaling.

Our patient also had some clinical features characteristic of BHDS, such as flesh-colored facial papules, acrochordonlike lesions, and chromophobe renal cell carcinoma.¹¹ Birt-Hogg-Dubé syndrome most often is caused by an autosomal-dominant germline mutation in FLCN, a tumor suppressor gene.¹¹ Interestingly, FLCN interacts with AMP-activated protein kinase to help regulate mTOR signaling, which may explain phenotypic similarities seen in CS and BHDS.¹²

Because the PHTS disorders and BHDS result in similar functional consequences on the mTOR signaling pathway, patients can present with overlapping clinical features that may be diagnostically challenging. Management includes patient education regarding cancer risk, surveillance for early detection of malignancy, and genetic counseling for family members.² It is important for clinicians to appreciate phenotypic similarities between PHTS and other disorders affecting mTOR signaling to prevent delays in diagnosis.

To the Editor:

PTEN hamartoma tumor syndrome (PHTS) encompasses a spectrum of disorders that most commonly are caused by autosomal-dominant germline mutations in the phosphatase and tensin homolog, PTEN, tumor suppressor gene on chromosome 10q23. We describe a patient who presented with clinical features of PHTS and Birt-Hogg-Dubé syndrome (BHDS). Because the genetic mutations associated with both PHTS and BHDS result in altered mammalian target of rapamycin (mTOR) signaling, patients may have overlapping phenotypic features.

A 51-year-old man with a history of multiple carcinomas presented for evaluation of flesh-colored papules on the cheeks, nose, tongue, and hands, in addition to numerous skin tags on the neck, axillae, and lower abdomen bilaterally. His medical history was notable for several nasal and gastrointestinal tract polyps, chromophobe renal cell carcinoma, cutaneous lipomas, atypical carcinoid syndrome of the right lung, and a multinodular thyroid. His family history was notable for small cell lung cancer in his father, breast cancer and pancreatic cancer in his maternal aunt, esophageal cancer in his maternal grandfather, and celiac disease in his daughter.

Clinical examination revealed flesh-colored, dome-shaped papules measuring 1 to 2 mm in diameter on the nose and cheeks (Figure 1). He had hyperkeratotic papules on the dorsal fingers, consistent with acral keratoses. Additionally, multiple flesh-colored papules with a cobblestonelike appearance were noted on the oral mucosa (Figure 2). Other findings included pedunculated papules on the neck, axillae, and lower abdomen bilaterally, consistent with fibroepithelial polyps, as well as hyperpigmented velvety plaques on the axillae, characteristic of acanthosis nigricans (Figure 3). A shave biopsy of a papule on the right cheek revealed a proliferation of plump stellate fibroblasts, small blood vessels, and thick collagen bundles, characteristic of a fibrous papule (Figure 4).

Differential diagnoses for our patient included BHDS and Cowden syndrome (CS). Due to the combination of extensive family history of multiorgan cancers as well as the clinical findings, he was referred to a geneticist for further evaluation. Genetic analysis was positive for a heterozygous mutation variant of uncertain significance in the PTEN gene.

The PHTS disorders include CS, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, and Proteus-like syndrome (Table).^1-9 Our patient’s clinical findings were indicative of CS, a rare genodermatosis characterized by multiple hamartomas and neoplasms of ectodermal, mesodermal, and endodermal origin.¹ Most CS patients develop trichilemmomas of the central face, mucocutaneous papillomatous papules, and acral and plantar keratoses by the third decade of life.¹ Importantly, CS patients have an increased risk for breast, thyroid, renal, endometrial, and colorectal cancers, as well as melanoma, with estimated lifetime risks of 85%, 35%, 33%, 28%, 9%, and 6%, respectively.^2,10

Regarding the pathophysiology of PHTS disorders, PTEN encodes a phosphatase that inhibits phosphoinositide 3-kinase/Akt and mTOR signaling pathways, thereby controlling cell proliferation, cell-cycle progression, and apoptosis.^2,3 Loss of PTEN function, as seen in CS patients, results in an increased risk for cancer.² Other genetic diseases, including juvenile polyposis syndrome, Proteus syndrome, tuberous sclerosis, and Peutz-Jeghers syndrome, have phenotypic similarities to PHTS.³ Specifically, loss-of-function mutations of TSC1 and TSC2, tumor suppressor genes associated with tuberous sclerosis, similarly result in dysregulation of mTOR signaling.

Our patient also had some clinical features characteristic of BHDS, such as flesh-colored facial papules, acrochordonlike lesions, and chromophobe renal cell carcinoma.¹¹ Birt-Hogg-Dubé syndrome most often is caused by an autosomal-dominant germline mutation in FLCN, a tumor suppressor gene.¹¹ Interestingly, FLCN interacts with AMP-activated protein kinase to help regulate mTOR signaling, which may explain phenotypic similarities seen in CS and BHDS.¹²

Because the PHTS disorders and BHDS result in similar functional consequences on the mTOR signaling pathway, patients can present with overlapping clinical features that may be diagnostically challenging. Management includes patient education regarding cancer risk, surveillance for early detection of malignancy, and genetic counseling for family members.² It is important for clinicians to appreciate phenotypic similarities between PHTS and other disorders affecting mTOR signaling to prevent delays in diagnosis.