The vast majority of melatonin gummies sold in the United States may contain up to 347% more melatonin than is listed on the label, and some products also contain cannabidiol. New data may explain the recent massive jump in pediatric hospitalizations.
 

Thenvestigators found that consuming some products as directed could expose consumers, including children, to doses that are 40-130 times greater than what’s recommended.

“The results were quite shocking,” lead researcher Pieter Cohen, MD, with Harvard Medical School, Boston, and Cambridge Health Alliance, Somerville, Mass., said in an interview.

“Melatonin gummies contained up to 347% more melatonin than what was listed on the label, and some products also contained cannabidiol; in one brand of melatonin gummies, there was zero melatonin, just CBD,” Dr. Cohen said.

The study was published online in JAMA.
 

530% jump in pediatric hospitalizations

Melatonin products are not approved by the Food and Drug Administration but are sold over the counter or online.

Previous research from JAMA has shown the use of melatonin has increased over the past 2 decades among people of all ages.

With increased use has come a spike in reports of melatonin overdose, calls to poison control centers, and related ED visits for children.

Federal data show the number of U.S. children who unintentionally ingested melatonin supplements jumped 530% from 2012 to 2021. More than 4,000 of the reported ingestions led to a hospital stay; 287 children required intensive care, and two children died.

It was unclear why melatonin supplements were causing these harms, which led Dr. Cohen’s team to analyze 25 unique brands of “melatonin” gummies purchased online.

One product didn’t contain any melatonin but did contain 31.3 mg of CBD.

In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving. The actual quantity of melatonin ranged from 74% to 347% of the labeled quantity, the researchers found.

They note that for a young adult who takes as little as 0.1-0.3 mg of melatonin, plasma concentrations can increase into the normal night-time range.

Of the 25 products (88%) analyzed, 22 were inaccurately labeled, and only 3 (12%) contained a quantity of melatonin that was within 10% (plus or minus) of the declared quantity.

Five products listed CBD as an ingredient. The listed quantity ranged from 10.6 mg to 31.3 mg per serving, although the actual quantity of CBD ranged from 104% to 118% of the labeled quantity.
 

Inquire about use in kids

A limitation of the study is that only one sample of each brand was analyzed, and only gummies were analyzed. It is not known whether the results are generalizable to melatonin products sold as tablets and capsules in the United States or whether the quantity of melatonin within an individual brand may vary from batch to batch.

A recent study from Canada showed similar results. In an analysis of 16 Canadian melatonin brands, the actual dose of melatonin ranged from 17% to 478% of the declared quantity.

It’s estimated that more than 1% of all U.S. children use melatonin supplements, most commonly for sleep, stress, and relaxation.

“Given new research as to the excessive quantities of melatonin in gummies, caution should be used if considering their use,” said Dr. Cohen.

“It’s important to inquire about melatonin use when caring for children, particularly when parents express concerns about their child’s sleep,” he added.

The American Academy of Sleep Medicine recently issued a health advisory encouraging parents to talk to a health care professional before giving melatonin or any supplement to children.
 

Children don’t need melatonin

Commenting on the study, Michael Breus, PhD, clinical psychologist and founder of TheSleepDoctor.com, agreed that analyzing only one sample of each brand is a key limitation “because supplements are made in batches, and gummies in particular are difficult to distribute the active ingredient evenly.

“But even with that being said, 88% of them were labeled incorrectly, so even if there were a few single-sample issues, I kind of doubt its all of them,” Dr. Breus said.

“Kids as a general rule do not need melatonin. Their brains make almost four times the necessary amount already. If you start giving kids pills to help them sleep, then they start to have a pill problem, causing another issue,” Dr. Breus added.

“Most children’s falling asleep and staying sleep issues can be treated with behavioral measures like cognitive-behavioral therapy for insomnia,” he said.

The study had no specific funding. Dr. Cohen has received research support from Consumers Union and PEW Charitable Trusts and royalties from UptoDate. Dr. Breus disclosed no relevant financial relationships.

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

The vast majority of melatonin gummies sold in the United States may contain up to 347% more melatonin than is listed on the label, and some products also contain cannabidiol. New data may explain the recent massive jump in pediatric hospitalizations.
 

Thenvestigators found that consuming some products as directed could expose consumers, including children, to doses that are 40-130 times greater than what’s recommended.

“The results were quite shocking,” lead researcher Pieter Cohen, MD, with Harvard Medical School, Boston, and Cambridge Health Alliance, Somerville, Mass., said in an interview.

“Melatonin gummies contained up to 347% more melatonin than what was listed on the label, and some products also contained cannabidiol; in one brand of melatonin gummies, there was zero melatonin, just CBD,” Dr. Cohen said.

The study was published online in JAMA.
 

530% jump in pediatric hospitalizations

Melatonin products are not approved by the Food and Drug Administration but are sold over the counter or online.

Previous research from JAMA has shown the use of melatonin has increased over the past 2 decades among people of all ages.

With increased use has come a spike in reports of melatonin overdose, calls to poison control centers, and related ED visits for children.

Federal data show the number of U.S. children who unintentionally ingested melatonin supplements jumped 530% from 2012 to 2021. More than 4,000 of the reported ingestions led to a hospital stay; 287 children required intensive care, and two children died.

It was unclear why melatonin supplements were causing these harms, which led Dr. Cohen’s team to analyze 25 unique brands of “melatonin” gummies purchased online.

One product didn’t contain any melatonin but did contain 31.3 mg of CBD.

In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving. The actual quantity of melatonin ranged from 74% to 347% of the labeled quantity, the researchers found.

They note that for a young adult who takes as little as 0.1-0.3 mg of melatonin, plasma concentrations can increase into the normal night-time range.

Of the 25 products (88%) analyzed, 22 were inaccurately labeled, and only 3 (12%) contained a quantity of melatonin that was within 10% (plus or minus) of the declared quantity.

Five products listed CBD as an ingredient. The listed quantity ranged from 10.6 mg to 31.3 mg per serving, although the actual quantity of CBD ranged from 104% to 118% of the labeled quantity.
 

Inquire about use in kids

A limitation of the study is that only one sample of each brand was analyzed, and only gummies were analyzed. It is not known whether the results are generalizable to melatonin products sold as tablets and capsules in the United States or whether the quantity of melatonin within an individual brand may vary from batch to batch.

A recent study from Canada showed similar results. In an analysis of 16 Canadian melatonin brands, the actual dose of melatonin ranged from 17% to 478% of the declared quantity.

It’s estimated that more than 1% of all U.S. children use melatonin supplements, most commonly for sleep, stress, and relaxation.

“Given new research as to the excessive quantities of melatonin in gummies, caution should be used if considering their use,” said Dr. Cohen.

“It’s important to inquire about melatonin use when caring for children, particularly when parents express concerns about their child’s sleep,” he added.

The American Academy of Sleep Medicine recently issued a health advisory encouraging parents to talk to a health care professional before giving melatonin or any supplement to children.
 

Children don’t need melatonin

Commenting on the study, Michael Breus, PhD, clinical psychologist and founder of TheSleepDoctor.com, agreed that analyzing only one sample of each brand is a key limitation “because supplements are made in batches, and gummies in particular are difficult to distribute the active ingredient evenly.

“But even with that being said, 88% of them were labeled incorrectly, so even if there were a few single-sample issues, I kind of doubt its all of them,” Dr. Breus said.

“Kids as a general rule do not need melatonin. Their brains make almost four times the necessary amount already. If you start giving kids pills to help them sleep, then they start to have a pill problem, causing another issue,” Dr. Breus added.

“Most children’s falling asleep and staying sleep issues can be treated with behavioral measures like cognitive-behavioral therapy for insomnia,” he said.

The study had no specific funding. Dr. Cohen has received research support from Consumers Union and PEW Charitable Trusts and royalties from UptoDate. Dr. Breus disclosed no relevant financial relationships.

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

The vast majority of melatonin gummies sold in the United States may contain up to 347% more melatonin than is listed on the label, and some products also contain cannabidiol. New data may explain the recent massive jump in pediatric hospitalizations.
 

Thenvestigators found that consuming some products as directed could expose consumers, including children, to doses that are 40-130 times greater than what’s recommended.

“The results were quite shocking,” lead researcher Pieter Cohen, MD, with Harvard Medical School, Boston, and Cambridge Health Alliance, Somerville, Mass., said in an interview.

“Melatonin gummies contained up to 347% more melatonin than what was listed on the label, and some products also contained cannabidiol; in one brand of melatonin gummies, there was zero melatonin, just CBD,” Dr. Cohen said.

The study was published online in JAMA.
 

530% jump in pediatric hospitalizations

Melatonin products are not approved by the Food and Drug Administration but are sold over the counter or online.

Previous research from JAMA has shown the use of melatonin has increased over the past 2 decades among people of all ages.

With increased use has come a spike in reports of melatonin overdose, calls to poison control centers, and related ED visits for children.

Federal data show the number of U.S. children who unintentionally ingested melatonin supplements jumped 530% from 2012 to 2021. More than 4,000 of the reported ingestions led to a hospital stay; 287 children required intensive care, and two children died.

It was unclear why melatonin supplements were causing these harms, which led Dr. Cohen’s team to analyze 25 unique brands of “melatonin” gummies purchased online.

One product didn’t contain any melatonin but did contain 31.3 mg of CBD.

In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving. The actual quantity of melatonin ranged from 74% to 347% of the labeled quantity, the researchers found.

They note that for a young adult who takes as little as 0.1-0.3 mg of melatonin, plasma concentrations can increase into the normal night-time range.

Of the 25 products (88%) analyzed, 22 were inaccurately labeled, and only 3 (12%) contained a quantity of melatonin that was within 10% (plus or minus) of the declared quantity.

Five products listed CBD as an ingredient. The listed quantity ranged from 10.6 mg to 31.3 mg per serving, although the actual quantity of CBD ranged from 104% to 118% of the labeled quantity.
 

Inquire about use in kids

A limitation of the study is that only one sample of each brand was analyzed, and only gummies were analyzed. It is not known whether the results are generalizable to melatonin products sold as tablets and capsules in the United States or whether the quantity of melatonin within an individual brand may vary from batch to batch.

A recent study from Canada showed similar results. In an analysis of 16 Canadian melatonin brands, the actual dose of melatonin ranged from 17% to 478% of the declared quantity.

It’s estimated that more than 1% of all U.S. children use melatonin supplements, most commonly for sleep, stress, and relaxation.

“Given new research as to the excessive quantities of melatonin in gummies, caution should be used if considering their use,” said Dr. Cohen.

“It’s important to inquire about melatonin use when caring for children, particularly when parents express concerns about their child’s sleep,” he added.

The American Academy of Sleep Medicine recently issued a health advisory encouraging parents to talk to a health care professional before giving melatonin or any supplement to children.
 

Children don’t need melatonin

Commenting on the study, Michael Breus, PhD, clinical psychologist and founder of TheSleepDoctor.com, agreed that analyzing only one sample of each brand is a key limitation “because supplements are made in batches, and gummies in particular are difficult to distribute the active ingredient evenly.

“But even with that being said, 88% of them were labeled incorrectly, so even if there were a few single-sample issues, I kind of doubt its all of them,” Dr. Breus said.

“Kids as a general rule do not need melatonin. Their brains make almost four times the necessary amount already. If you start giving kids pills to help them sleep, then they start to have a pill problem, causing another issue,” Dr. Breus added.

“Most children’s falling asleep and staying sleep issues can be treated with behavioral measures like cognitive-behavioral therapy for insomnia,” he said.

The study had no specific funding. Dr. Cohen has received research support from Consumers Union and PEW Charitable Trusts and royalties from UptoDate. Dr. Breus disclosed no relevant financial relationships.

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

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.^1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.³ As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.⁴

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.⁵ Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,⁶ an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,^7,8 the COVIDSKIN registry of the French Dermatology Society,⁹ and the Italian registry.¹⁰ Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)⁵ and Japan (0.56%),¹¹ compared with Europe (up to 20%).⁶ Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.¹² They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.^13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-19¹³ and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).^16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,¹⁹ which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.^20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.^17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.^26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.³⁰

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.^31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.³³

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.³⁴

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).^53,54

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.⁵⁵ Psoriasis and acrodermatitis continua of Hallopeau,⁵⁶ which may progress into generalized, pustular, or erythrodermic forms,⁵⁷ have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.⁵⁷ Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.⁵⁸ The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.⁵⁹ Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,⁶⁰ possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.⁶¹ Lupus erythematosus, which may relapse in the form of Rowell syndrome,⁶² and livedoid vasculopathy⁶³ also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,⁴ an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.^64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.⁶⁵ Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.⁷⁰ Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.⁷⁰
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.⁷⁰

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.⁷⁰

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.⁷⁰

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.⁷⁰

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.⁷¹

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.⁷²

• Chilblainlike lesions: several such cases have been reported so far⁷³; they constitute 0.03% of postvaccination reactions.⁷⁰ Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.^73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.⁷⁶

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).⁷⁰

• Severe reactions: these include acute generalized exanthematous pustulosis⁷⁷ and Stevens-Johnson syndrome.⁷⁸ One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,^79,80 leukocytoclastic vasculitis,^81,82 lymphocytic⁸³ or urticarial⁸⁴ vasculitis, Sweet syndrome,⁸⁵ lupus erythematosus, dermatomyositis,^86,87 alopecia,^37,88 infection with Trichophyton rubrum,⁸⁹ Grover disease,⁹⁰ and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30⁺], and de novo development of lymphomatoid papulosis).⁹¹

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.⁹² Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

To the Editor:

Hailey-Hailey disease (HHD)(also known as familial benign chronic pemphigus) is an inherited autosomal-dominant condition in the family of chronic bullous diseases. It is characterized by flaccid blisters, erosions, and macerated vegetative plaques with a predilection for intertriginous sites. Lesions often are weeping, painful, pruritic, and malodorous, leading to decreased quality of life for patients. Complications of this chronic disease include an increased risk for secondary infection and malignant transformation to squamous cell carcinoma.¹

Treatment of HHD remains difficult. Topical steroids, oral steroids, and ablative techniques such as dermabrasion and ablative lasers are the most widely reported therapies. OnabotulinumtoxinA has been described as a successful treatment for patients with HHD, including for disease recalcitrant to other therapies.² We describe 2 patients with HHD who responded to treatment with intralesional onabotulinumtoxinA injections with and without adjuvant oral glycopyrrolate.

A 54-year-old woman presented with painful flaccid blisters under the breasts (Figure 1A) and in the axillae and groin of 3 weeks’ duration. Biopsy results from this initial visit were consistent with a diagnosis of HHD. The patient reported that the onset of blisters coincided with episodes of severe hyperhidrosis. Therapy with topical and oral steroids, antifungals, antibiotics, and topical aluminum chloride failed to achieve adequate disease control. After a discussion of the risks and benefits, the patient agreed to treatment with injections of onabotulinumtoxinA. At months 0, 3, and 6, the patient received 50 U of onabotulinumtoxinA under the breasts and in the axillae and the groin, for a total of 250 U each session. Each injection consisted of 2.5 U of onabotulinumtoxinA spaced 1-cm apart. Clinical improvement was noted within 2 weeks of initiating neuromodulator therapy. Follow-up at 9 months demonstrated improvement (Figure 1B); however, complete clearance was not achieved, and the patient required ongoing treatment with onabotulinumtoxinA every 3 months.

A 43-year-old woman presented with erythematous eroded plaques of the antecubital fossae, axillae, and chest (Figure 2A) of 10 years’ duration. A biopsy from an outside provider demonstrated findings consistent with a diagnosis of HHD. Prior therapies included topical and oral steroids. After a discussion of the risks and benefits, the patient was treated with onabotulinumtoxinA injections in combination with oral glycopyrrolate 5 mg daily. She received 30 U of onabotulinumtoxinA to each axilla, 10 U to each antecubital fossa, and 20 U to the central chest. At 1 month follow-up, the patient reported great improvement in lesion burden and active disease (Figure 2B). Nine months after treatment, her HHD was in complete remission with glycopyrrolate alone and she did not require further therapy with onabotulinumtoxinA.

Hailey-Hailey disease has been attributed to mutations of the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1, that lead to aberrations in calcium signaling and subsequent impaired adhesion between keratinocytes.² These compromised cell-cell connections are worsened by the presence of humidity, causing further acantholysis. Chemical denervation of the sweat glands with botulinum toxin has been postulated to improve HHD by reducing moisture in vulnerable areas. Our 2 cases add to the existing literature documenting tangible clinical results that correlate with this hypothesis.^3-5

Our second case is unique in that the patient achieved rapid improvement using a combination of onabotulinumtoxinA and glycopyrrolate therapy. Both onabotulinumtoxinA and glycopyrrolate inhibit acetylcholine signaling that is required for sweat production; however, each drug exerts its effect on different zones of the cholinergic pathway, which may partially account for the synergistic effect of onabotulinumtoxinA and glycopyrrolate to improve HHD, as sweating is dually inhibited by the 2 drugs. Additionally, the combined local and systemic administration of these anticholinergic medications may further potentiate the sweat blockade, particularly in areas most prone to disease.

Botulinum toxin for the treatment of HHD is an effective monotherapy. The addition of an oral anticholinergic to local neuromodulator injections may speed symptom resolution and sustain disease remission. Further studies to evaluate this combination are warranted.

To the Editor:

Hailey-Hailey disease (HHD)(also known as familial benign chronic pemphigus) is an inherited autosomal-dominant condition in the family of chronic bullous diseases. It is characterized by flaccid blisters, erosions, and macerated vegetative plaques with a predilection for intertriginous sites. Lesions often are weeping, painful, pruritic, and malodorous, leading to decreased quality of life for patients. Complications of this chronic disease include an increased risk for secondary infection and malignant transformation to squamous cell carcinoma.¹

Treatment of HHD remains difficult. Topical steroids, oral steroids, and ablative techniques such as dermabrasion and ablative lasers are the most widely reported therapies. OnabotulinumtoxinA has been described as a successful treatment for patients with HHD, including for disease recalcitrant to other therapies.² We describe 2 patients with HHD who responded to treatment with intralesional onabotulinumtoxinA injections with and without adjuvant oral glycopyrrolate.

A 54-year-old woman presented with painful flaccid blisters under the breasts (Figure 1A) and in the axillae and groin of 3 weeks’ duration. Biopsy results from this initial visit were consistent with a diagnosis of HHD. The patient reported that the onset of blisters coincided with episodes of severe hyperhidrosis. Therapy with topical and oral steroids, antifungals, antibiotics, and topical aluminum chloride failed to achieve adequate disease control. After a discussion of the risks and benefits, the patient agreed to treatment with injections of onabotulinumtoxinA. At months 0, 3, and 6, the patient received 50 U of onabotulinumtoxinA under the breasts and in the axillae and the groin, for a total of 250 U each session. Each injection consisted of 2.5 U of onabotulinumtoxinA spaced 1-cm apart. Clinical improvement was noted within 2 weeks of initiating neuromodulator therapy. Follow-up at 9 months demonstrated improvement (Figure 1B); however, complete clearance was not achieved, and the patient required ongoing treatment with onabotulinumtoxinA every 3 months.

A 43-year-old woman presented with erythematous eroded plaques of the antecubital fossae, axillae, and chest (Figure 2A) of 10 years’ duration. A biopsy from an outside provider demonstrated findings consistent with a diagnosis of HHD. Prior therapies included topical and oral steroids. After a discussion of the risks and benefits, the patient was treated with onabotulinumtoxinA injections in combination with oral glycopyrrolate 5 mg daily. She received 30 U of onabotulinumtoxinA to each axilla, 10 U to each antecubital fossa, and 20 U to the central chest. At 1 month follow-up, the patient reported great improvement in lesion burden and active disease (Figure 2B). Nine months after treatment, her HHD was in complete remission with glycopyrrolate alone and she did not require further therapy with onabotulinumtoxinA.

Hailey-Hailey disease has been attributed to mutations of the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1, that lead to aberrations in calcium signaling and subsequent impaired adhesion between keratinocytes.² These compromised cell-cell connections are worsened by the presence of humidity, causing further acantholysis. Chemical denervation of the sweat glands with botulinum toxin has been postulated to improve HHD by reducing moisture in vulnerable areas. Our 2 cases add to the existing literature documenting tangible clinical results that correlate with this hypothesis.^3-5

Our second case is unique in that the patient achieved rapid improvement using a combination of onabotulinumtoxinA and glycopyrrolate therapy. Both onabotulinumtoxinA and glycopyrrolate inhibit acetylcholine signaling that is required for sweat production; however, each drug exerts its effect on different zones of the cholinergic pathway, which may partially account for the synergistic effect of onabotulinumtoxinA and glycopyrrolate to improve HHD, as sweating is dually inhibited by the 2 drugs. Additionally, the combined local and systemic administration of these anticholinergic medications may further potentiate the sweat blockade, particularly in areas most prone to disease.

Botulinum toxin for the treatment of HHD is an effective monotherapy. The addition of an oral anticholinergic to local neuromodulator injections may speed symptom resolution and sustain disease remission. Further studies to evaluate this combination are warranted.

To the Editor:

Hailey-Hailey disease (HHD)(also known as familial benign chronic pemphigus) is an inherited autosomal-dominant condition in the family of chronic bullous diseases. It is characterized by flaccid blisters, erosions, and macerated vegetative plaques with a predilection for intertriginous sites. Lesions often are weeping, painful, pruritic, and malodorous, leading to decreased quality of life for patients. Complications of this chronic disease include an increased risk for secondary infection and malignant transformation to squamous cell carcinoma.¹

Treatment of HHD remains difficult. Topical steroids, oral steroids, and ablative techniques such as dermabrasion and ablative lasers are the most widely reported therapies. OnabotulinumtoxinA has been described as a successful treatment for patients with HHD, including for disease recalcitrant to other therapies.² We describe 2 patients with HHD who responded to treatment with intralesional onabotulinumtoxinA injections with and without adjuvant oral glycopyrrolate.

A 54-year-old woman presented with painful flaccid blisters under the breasts (Figure 1A) and in the axillae and groin of 3 weeks’ duration. Biopsy results from this initial visit were consistent with a diagnosis of HHD. The patient reported that the onset of blisters coincided with episodes of severe hyperhidrosis. Therapy with topical and oral steroids, antifungals, antibiotics, and topical aluminum chloride failed to achieve adequate disease control. After a discussion of the risks and benefits, the patient agreed to treatment with injections of onabotulinumtoxinA. At months 0, 3, and 6, the patient received 50 U of onabotulinumtoxinA under the breasts and in the axillae and the groin, for a total of 250 U each session. Each injection consisted of 2.5 U of onabotulinumtoxinA spaced 1-cm apart. Clinical improvement was noted within 2 weeks of initiating neuromodulator therapy. Follow-up at 9 months demonstrated improvement (Figure 1B); however, complete clearance was not achieved, and the patient required ongoing treatment with onabotulinumtoxinA every 3 months.

A 43-year-old woman presented with erythematous eroded plaques of the antecubital fossae, axillae, and chest (Figure 2A) of 10 years’ duration. A biopsy from an outside provider demonstrated findings consistent with a diagnosis of HHD. Prior therapies included topical and oral steroids. After a discussion of the risks and benefits, the patient was treated with onabotulinumtoxinA injections in combination with oral glycopyrrolate 5 mg daily. She received 30 U of onabotulinumtoxinA to each axilla, 10 U to each antecubital fossa, and 20 U to the central chest. At 1 month follow-up, the patient reported great improvement in lesion burden and active disease (Figure 2B). Nine months after treatment, her HHD was in complete remission with glycopyrrolate alone and she did not require further therapy with onabotulinumtoxinA.

Hailey-Hailey disease has been attributed to mutations of the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1, that lead to aberrations in calcium signaling and subsequent impaired adhesion between keratinocytes.² These compromised cell-cell connections are worsened by the presence of humidity, causing further acantholysis. Chemical denervation of the sweat glands with botulinum toxin has been postulated to improve HHD by reducing moisture in vulnerable areas. Our 2 cases add to the existing literature documenting tangible clinical results that correlate with this hypothesis.^3-5

Our second case is unique in that the patient achieved rapid improvement using a combination of onabotulinumtoxinA and glycopyrrolate therapy. Both onabotulinumtoxinA and glycopyrrolate inhibit acetylcholine signaling that is required for sweat production; however, each drug exerts its effect on different zones of the cholinergic pathway, which may partially account for the synergistic effect of onabotulinumtoxinA and glycopyrrolate to improve HHD, as sweating is dually inhibited by the 2 drugs. Additionally, the combined local and systemic administration of these anticholinergic medications may further potentiate the sweat blockade, particularly in areas most prone to disease.

Botulinum toxin for the treatment of HHD is an effective monotherapy. The addition of an oral anticholinergic to local neuromodulator injections may speed symptom resolution and sustain disease remission. Further studies to evaluate this combination are warranted.

Narcissists appear to be everywhere. A few minutes on the Internet shows the dangers of narcissistic romantic partners, friends, and employers. Identifying and limiting the reach of their manipulative and self-centered endeavors is cast as both urgent and necessary. The destructive powers of the narcissistic mother are viewed as especially in need of remedy, and any bookstore can reveal the risks they pose: “Will I Ever Be Good Enough? Healing the Daughters of Narcissistic Mothers;” “You’re Not Crazy – It’s Your Mother: Freedom for Daughters of Narcissistic Mothers;” “Healing for Daughters of Narcissistic Mothers: A Practical Guide on How to Recover from the Childhood Trauma of Toxic Relationship with Your Mother and How You Can Handle Her Abuse Now As An Adult” – to name just a few (there are more).

As a psychologist specializing in parental estrangement, I (Dr. Coleman) regularly see letters from adult children explaining their discovery-through-therapy that their mother is a narcissist. The proclamation often comes when the therapist has never met the mother. Typically, the discovery is presented as a justification for ending the relationship with the parent. While these mothers could rightly be accused of being anxious, over-involved, depressed, or hurt by the lack of gratitude or reciprocity, the vast majority are not narcissists.

Blaming mothers has a long reach. Mothers have been blamed for causing schizophrenia, autism, homosexuality, and effeminacy in men. While we used to call people selfish and “controlling,” narcissism is a more consequential label as it confers diagnostic validity from the mental health profession. Worse, it suggests an individual beyond reach, where the only answer is distance, containment, or estrangement.

The rise of the narcissistic mother comes during a time when, for the past 4 decades, the average working mother spends more time with her children than stay-at-home moms did in the supposed halcyon days of the 1960s’ middle class, before “parenting” was a common term. A variety of economists and sociologists observed that an increase in parental effort became necessary to launch children into adulthood given the retreat of governmental and corporate support for parents that began in the 1980s.

“The financial and emotional burden on families has grown in ways that were almost unimaginable just a half-century ago,” writes the University of Pennsylvania sociologist Frank Furstenberg in “On a New Schedule: Transitions to Adulthood and Family Change.” In addition, a view of children as vulnerable and in need of intense parental investment gained momentum over the course of the 20th century and has continued unabated into the present. As a result, an environment of intense maternal preoccupation, worry, guilt, and involvement with children’s grades, safety, health, and emotional states – referred to as “helicopter” and “tiger” mothering – grew into the norm across the classes.

While prior generations of parents could, by today’s standards, be viewed as being insufficiently involved, today’s parents have become “over-involved” – aided by the ability of parents to be in constant contact with their adult children through technology. While this shift to a more hands-on, more conscientious parenting has been a boon to parent–adult child relationships in the main, the downside has meant, for some, too much of a good thing. From that perspective, pathologizing a mother’s involvement or her expressions of hurt for that child’s lack of availability provides a shield against the child’s feelings of guilt or obligation.

Diagnoses can serve a social purpose: They can allow individuals to use the authority of our profession to decide who to be close to and who to let go. They can provide insulation against feelings of obligation or guilt. They create a way to label behavior as dysfunctional that in other eras or cultures would be considered normal, even valued. To that extent, diagnoses don’t occur in a cultural void. They are inextricably tied to larger ideals, be they individualistic – as exists in the United States – or collectivist, as exists in many other parts of the world.

While we have decided what parents owe our children, it is unclear what parents might ask in return. To that end, mothers who want more interest, availability, or gratitude today are vulnerable to being cast as selfish, uncaring, needy, and controlling. They can now be viewed as failing in their task of selfless devotion. Their desires for closeness or repair can be regarded as incompatible with the quest for the adult child’s self-fulfillment and identity; her identification with her children too great a barrier to their individuation.

There may well be good reasons to estrange family members for their intolerable behaviors, especially ones who have threatened personal safety. Yet, while there are plenty of problematic parents, few meet the diagnostic criteria of narcissistic personality disorder. More important, such labels can discourage a discussion of boundaries that both the parents and the adult children might find acceptable – which sometimes means asking family members to tolerate behavior or individuals not to their liking.

Diagnoses carry enormous social weight and can facilitate estrangements or negativity to mothers that are far more workable than our patients’ characterization of them might lead them or us to believe. Wrongly labeling mothers as narcissists greatly oversimplifies their lives and struggles; it devalues their years of love and dedication, however flawed; and it weakens the fabric of connection that could otherwise exist. Rather than provide a path toward compassion or understanding, “narcissistic mother” just becomes the latest form of mommy shaming.

Dr. Coleman is a clinical psychologist and author of “Rules of Estrangement: Why Adult Children Cut Ties and How to Heal the Conflict” (New York: Penguin Random House, 2021). Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore.

Narcissists appear to be everywhere. A few minutes on the Internet shows the dangers of narcissistic romantic partners, friends, and employers. Identifying and limiting the reach of their manipulative and self-centered endeavors is cast as both urgent and necessary. The destructive powers of the narcissistic mother are viewed as especially in need of remedy, and any bookstore can reveal the risks they pose: “Will I Ever Be Good Enough? Healing the Daughters of Narcissistic Mothers;” “You’re Not Crazy – It’s Your Mother: Freedom for Daughters of Narcissistic Mothers;” “Healing for Daughters of Narcissistic Mothers: A Practical Guide on How to Recover from the Childhood Trauma of Toxic Relationship with Your Mother and How You Can Handle Her Abuse Now As An Adult” – to name just a few (there are more).

As a psychologist specializing in parental estrangement, I (Dr. Coleman) regularly see letters from adult children explaining their discovery-through-therapy that their mother is a narcissist. The proclamation often comes when the therapist has never met the mother. Typically, the discovery is presented as a justification for ending the relationship with the parent. While these mothers could rightly be accused of being anxious, over-involved, depressed, or hurt by the lack of gratitude or reciprocity, the vast majority are not narcissists.

Blaming mothers has a long reach. Mothers have been blamed for causing schizophrenia, autism, homosexuality, and effeminacy in men. While we used to call people selfish and “controlling,” narcissism is a more consequential label as it confers diagnostic validity from the mental health profession. Worse, it suggests an individual beyond reach, where the only answer is distance, containment, or estrangement.

The rise of the narcissistic mother comes during a time when, for the past 4 decades, the average working mother spends more time with her children than stay-at-home moms did in the supposed halcyon days of the 1960s’ middle class, before “parenting” was a common term. A variety of economists and sociologists observed that an increase in parental effort became necessary to launch children into adulthood given the retreat of governmental and corporate support for parents that began in the 1980s.

“The financial and emotional burden on families has grown in ways that were almost unimaginable just a half-century ago,” writes the University of Pennsylvania sociologist Frank Furstenberg in “On a New Schedule: Transitions to Adulthood and Family Change.” In addition, a view of children as vulnerable and in need of intense parental investment gained momentum over the course of the 20th century and has continued unabated into the present. As a result, an environment of intense maternal preoccupation, worry, guilt, and involvement with children’s grades, safety, health, and emotional states – referred to as “helicopter” and “tiger” mothering – grew into the norm across the classes.

While prior generations of parents could, by today’s standards, be viewed as being insufficiently involved, today’s parents have become “over-involved” – aided by the ability of parents to be in constant contact with their adult children through technology. While this shift to a more hands-on, more conscientious parenting has been a boon to parent–adult child relationships in the main, the downside has meant, for some, too much of a good thing. From that perspective, pathologizing a mother’s involvement or her expressions of hurt for that child’s lack of availability provides a shield against the child’s feelings of guilt or obligation.

Diagnoses can serve a social purpose: They can allow individuals to use the authority of our profession to decide who to be close to and who to let go. They can provide insulation against feelings of obligation or guilt. They create a way to label behavior as dysfunctional that in other eras or cultures would be considered normal, even valued. To that extent, diagnoses don’t occur in a cultural void. They are inextricably tied to larger ideals, be they individualistic – as exists in the United States – or collectivist, as exists in many other parts of the world.

While we have decided what parents owe our children, it is unclear what parents might ask in return. To that end, mothers who want more interest, availability, or gratitude today are vulnerable to being cast as selfish, uncaring, needy, and controlling. They can now be viewed as failing in their task of selfless devotion. Their desires for closeness or repair can be regarded as incompatible with the quest for the adult child’s self-fulfillment and identity; her identification with her children too great a barrier to their individuation.

There may well be good reasons to estrange family members for their intolerable behaviors, especially ones who have threatened personal safety. Yet, while there are plenty of problematic parents, few meet the diagnostic criteria of narcissistic personality disorder. More important, such labels can discourage a discussion of boundaries that both the parents and the adult children might find acceptable – which sometimes means asking family members to tolerate behavior or individuals not to their liking.

Diagnoses carry enormous social weight and can facilitate estrangements or negativity to mothers that are far more workable than our patients’ characterization of them might lead them or us to believe. Wrongly labeling mothers as narcissists greatly oversimplifies their lives and struggles; it devalues their years of love and dedication, however flawed; and it weakens the fabric of connection that could otherwise exist. Rather than provide a path toward compassion or understanding, “narcissistic mother” just becomes the latest form of mommy shaming.

Dr. Coleman is a clinical psychologist and author of “Rules of Estrangement: Why Adult Children Cut Ties and How to Heal the Conflict” (New York: Penguin Random House, 2021). Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore.

Narcissists appear to be everywhere. A few minutes on the Internet shows the dangers of narcissistic romantic partners, friends, and employers. Identifying and limiting the reach of their manipulative and self-centered endeavors is cast as both urgent and necessary. The destructive powers of the narcissistic mother are viewed as especially in need of remedy, and any bookstore can reveal the risks they pose: “Will I Ever Be Good Enough? Healing the Daughters of Narcissistic Mothers;” “You’re Not Crazy – It’s Your Mother: Freedom for Daughters of Narcissistic Mothers;” “Healing for Daughters of Narcissistic Mothers: A Practical Guide on How to Recover from the Childhood Trauma of Toxic Relationship with Your Mother and How You Can Handle Her Abuse Now As An Adult” – to name just a few (there are more).

As a psychologist specializing in parental estrangement, I (Dr. Coleman) regularly see letters from adult children explaining their discovery-through-therapy that their mother is a narcissist. The proclamation often comes when the therapist has never met the mother. Typically, the discovery is presented as a justification for ending the relationship with the parent. While these mothers could rightly be accused of being anxious, over-involved, depressed, or hurt by the lack of gratitude or reciprocity, the vast majority are not narcissists.

Blaming mothers has a long reach. Mothers have been blamed for causing schizophrenia, autism, homosexuality, and effeminacy in men. While we used to call people selfish and “controlling,” narcissism is a more consequential label as it confers diagnostic validity from the mental health profession. Worse, it suggests an individual beyond reach, where the only answer is distance, containment, or estrangement.

The rise of the narcissistic mother comes during a time when, for the past 4 decades, the average working mother spends more time with her children than stay-at-home moms did in the supposed halcyon days of the 1960s’ middle class, before “parenting” was a common term. A variety of economists and sociologists observed that an increase in parental effort became necessary to launch children into adulthood given the retreat of governmental and corporate support for parents that began in the 1980s.

“The financial and emotional burden on families has grown in ways that were almost unimaginable just a half-century ago,” writes the University of Pennsylvania sociologist Frank Furstenberg in “On a New Schedule: Transitions to Adulthood and Family Change.” In addition, a view of children as vulnerable and in need of intense parental investment gained momentum over the course of the 20th century and has continued unabated into the present. As a result, an environment of intense maternal preoccupation, worry, guilt, and involvement with children’s grades, safety, health, and emotional states – referred to as “helicopter” and “tiger” mothering – grew into the norm across the classes.

While prior generations of parents could, by today’s standards, be viewed as being insufficiently involved, today’s parents have become “over-involved” – aided by the ability of parents to be in constant contact with their adult children through technology. While this shift to a more hands-on, more conscientious parenting has been a boon to parent–adult child relationships in the main, the downside has meant, for some, too much of a good thing. From that perspective, pathologizing a mother’s involvement or her expressions of hurt for that child’s lack of availability provides a shield against the child’s feelings of guilt or obligation.

Diagnoses can serve a social purpose: They can allow individuals to use the authority of our profession to decide who to be close to and who to let go. They can provide insulation against feelings of obligation or guilt. They create a way to label behavior as dysfunctional that in other eras or cultures would be considered normal, even valued. To that extent, diagnoses don’t occur in a cultural void. They are inextricably tied to larger ideals, be they individualistic – as exists in the United States – or collectivist, as exists in many other parts of the world.

While we have decided what parents owe our children, it is unclear what parents might ask in return. To that end, mothers who want more interest, availability, or gratitude today are vulnerable to being cast as selfish, uncaring, needy, and controlling. They can now be viewed as failing in their task of selfless devotion. Their desires for closeness or repair can be regarded as incompatible with the quest for the adult child’s self-fulfillment and identity; her identification with her children too great a barrier to their individuation.

There may well be good reasons to estrange family members for their intolerable behaviors, especially ones who have threatened personal safety. Yet, while there are plenty of problematic parents, few meet the diagnostic criteria of narcissistic personality disorder. More important, such labels can discourage a discussion of boundaries that both the parents and the adult children might find acceptable – which sometimes means asking family members to tolerate behavior or individuals not to their liking.

Diagnoses carry enormous social weight and can facilitate estrangements or negativity to mothers that are far more workable than our patients’ characterization of them might lead them or us to believe. Wrongly labeling mothers as narcissists greatly oversimplifies their lives and struggles; it devalues their years of love and dedication, however flawed; and it weakens the fabric of connection that could otherwise exist. Rather than provide a path toward compassion or understanding, “narcissistic mother” just becomes the latest form of mommy shaming.

Dr. Coleman is a clinical psychologist and author of “Rules of Estrangement: Why Adult Children Cut Ties and How to Heal the Conflict” (New York: Penguin Random House, 2021). Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore.

WASHINGTON –  Posttraumatic stress disorder (PTSD) is strongly linked to disordered eating, which in turn, impedes treatment for the anxiety disorder in new findings that underscore the need for better screening of eating disorder impairment (EDI).

“Eating-related and body-image concerns may be more prevalent than we think, and if not considered, these concerns can make psychotherapy treatment less effective,” study author Nick Powers, a doctoral student in clinical psychology, La Salle University, Philadelphia, told this news organization.

Nick Powers

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

Common bedfellows

Although many patients with PTSD also have an eating disorder, they are not always properly assessed for eating pathology and related functional impairment.

Some therapists don’t feel adequately equipped to target eating-related concerns in these patients and so may refer them to other providers. This, said Mr. Powers, can prolong symptoms and further distress patients.

Mr. Powers noted childhood physical or sexual abuse may affect eating patterns in patients with PTSD. “The evidence suggests these types of trauma exposure can be risk factors for the development of an eating disorder.”

Undiagnosed eating pathology may exacerbate functional impairment from PTSD and weaken the impact of evidence-based treatment.

Such patients are challenging to treat as they may not have the requisite skills to fully engage in exposure therapy, an evidence-based approach to treat PTSD, said Mr. Powers.

To determine whether PTSD would be significantly linked to greater eating disorder impairment (EDI) compared with other anxiety-related diagnoses and whether this would impair treatment, investigators studied 748 patients with an anxiety disorder who were attending a cognitive behavioral therapy (CBT) clinic. Anxiety disorders included PTSD, obsessive-compulsive disorder (OCD), social anxiety, and panic disorder.

Participants completed the 16-item Clinical Impairment Assessment (CIA) questionnaire, which includes questions about eating habits and feelings about food, body shape, and weight over the previous 4 weeks. Participants also reported anxiety symptom severity at the beginning, during, and end of treatment.
 

Need for better screening

Results showed that compared with those who had other anxiety disorders, patients with PTSD were three times more likely to have disordered eating (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.47-6.37; P = .003).

In addition, higher baseline CIA scores predicted poorer PTSD treatment outcome (beta = –1.4; 95% CI, –1.67 to –1.10; P < .01).

“Having higher baseline CIA scores meant that patients’ PTSD symptoms did not remit as strongly compared to those with lower scores,” said Mr. Powers.

Patients with both PTSD and an eating disorder may have difficulty with regulating emotions and tolerating distress, he said.

“They may use binge eating, purging, or food restriction as strategies to regulate emotions. These behaviors may allow patients to become numb to or avoid heightened emotions that come from having PTSD and an eating disorder.”

Prior research linked perfectionism tendencies to poorer response to PTSD treatment. Those with an eating disorder may share similar tendencies, said Mr. Powers.

“If someone is consistently thinking negatively about their eating or body to the point where it interrupts their functioning, they may not be as likely to fully engage with PTSD treatment,” he said.

Ideally, clinicians would screen all patients with PTSD for an eating disorder, said Mr. Powers. “If screening instruments aren’t feasible or available, even just inquiring about body image or history of maladaptive eating behaviors can be helpful.”

He added this could open up a conversation about a traumatic event in the patient’s past.
 

Confirmatory research

Commenting on the study, Karen S. Mitchell, PhD, clinical research psychologist, National Center for PTSD, VA Boston Healthcare System, and associate professor in psychiatry, Boston University, said she was “excited” to see this research.

Boston University

“Very few studies have examined the impact of baseline eating disorder symptoms on PTSD treatment outcomes or vice versa,” she said.

The study findings “add to the small but growing body of evidence suggesting that comorbid PTSD and eating disorder symptoms can impact recovery from each disorder,” she said.

She noted the importance of assessing comorbidity in patients presenting for treatment and of addressing comorbidity in both eating disorders and PTSD treatment. “But we need more research on how best to do this.”

Mr. Powers and Dr. Mitchell have reported no relevant financial relationships.
 

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

WASHINGTON –  Posttraumatic stress disorder (PTSD) is strongly linked to disordered eating, which in turn, impedes treatment for the anxiety disorder in new findings that underscore the need for better screening of eating disorder impairment (EDI).

“Eating-related and body-image concerns may be more prevalent than we think, and if not considered, these concerns can make psychotherapy treatment less effective,” study author Nick Powers, a doctoral student in clinical psychology, La Salle University, Philadelphia, told this news organization.

Nick Powers

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

Common bedfellows

Although many patients with PTSD also have an eating disorder, they are not always properly assessed for eating pathology and related functional impairment.

Some therapists don’t feel adequately equipped to target eating-related concerns in these patients and so may refer them to other providers. This, said Mr. Powers, can prolong symptoms and further distress patients.

Mr. Powers noted childhood physical or sexual abuse may affect eating patterns in patients with PTSD. “The evidence suggests these types of trauma exposure can be risk factors for the development of an eating disorder.”

Undiagnosed eating pathology may exacerbate functional impairment from PTSD and weaken the impact of evidence-based treatment.

Such patients are challenging to treat as they may not have the requisite skills to fully engage in exposure therapy, an evidence-based approach to treat PTSD, said Mr. Powers.

To determine whether PTSD would be significantly linked to greater eating disorder impairment (EDI) compared with other anxiety-related diagnoses and whether this would impair treatment, investigators studied 748 patients with an anxiety disorder who were attending a cognitive behavioral therapy (CBT) clinic. Anxiety disorders included PTSD, obsessive-compulsive disorder (OCD), social anxiety, and panic disorder.

Participants completed the 16-item Clinical Impairment Assessment (CIA) questionnaire, which includes questions about eating habits and feelings about food, body shape, and weight over the previous 4 weeks. Participants also reported anxiety symptom severity at the beginning, during, and end of treatment.
 

Need for better screening

Results showed that compared with those who had other anxiety disorders, patients with PTSD were three times more likely to have disordered eating (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.47-6.37; P = .003).

In addition, higher baseline CIA scores predicted poorer PTSD treatment outcome (beta = –1.4; 95% CI, –1.67 to –1.10; P < .01).

“Having higher baseline CIA scores meant that patients’ PTSD symptoms did not remit as strongly compared to those with lower scores,” said Mr. Powers.

Patients with both PTSD and an eating disorder may have difficulty with regulating emotions and tolerating distress, he said.

“They may use binge eating, purging, or food restriction as strategies to regulate emotions. These behaviors may allow patients to become numb to or avoid heightened emotions that come from having PTSD and an eating disorder.”

Prior research linked perfectionism tendencies to poorer response to PTSD treatment. Those with an eating disorder may share similar tendencies, said Mr. Powers.

“If someone is consistently thinking negatively about their eating or body to the point where it interrupts their functioning, they may not be as likely to fully engage with PTSD treatment,” he said.

Ideally, clinicians would screen all patients with PTSD for an eating disorder, said Mr. Powers. “If screening instruments aren’t feasible or available, even just inquiring about body image or history of maladaptive eating behaviors can be helpful.”

He added this could open up a conversation about a traumatic event in the patient’s past.
 

Confirmatory research

Commenting on the study, Karen S. Mitchell, PhD, clinical research psychologist, National Center for PTSD, VA Boston Healthcare System, and associate professor in psychiatry, Boston University, said she was “excited” to see this research.

Boston University

“Very few studies have examined the impact of baseline eating disorder symptoms on PTSD treatment outcomes or vice versa,” she said.

The study findings “add to the small but growing body of evidence suggesting that comorbid PTSD and eating disorder symptoms can impact recovery from each disorder,” she said.

She noted the importance of assessing comorbidity in patients presenting for treatment and of addressing comorbidity in both eating disorders and PTSD treatment. “But we need more research on how best to do this.”

Mr. Powers and Dr. Mitchell have reported no relevant financial relationships.
 

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

WASHINGTON –  Posttraumatic stress disorder (PTSD) is strongly linked to disordered eating, which in turn, impedes treatment for the anxiety disorder in new findings that underscore the need for better screening of eating disorder impairment (EDI).

“Eating-related and body-image concerns may be more prevalent than we think, and if not considered, these concerns can make psychotherapy treatment less effective,” study author Nick Powers, a doctoral student in clinical psychology, La Salle University, Philadelphia, told this news organization.

Nick Powers

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

Common bedfellows

Although many patients with PTSD also have an eating disorder, they are not always properly assessed for eating pathology and related functional impairment.

Some therapists don’t feel adequately equipped to target eating-related concerns in these patients and so may refer them to other providers. This, said Mr. Powers, can prolong symptoms and further distress patients.

Mr. Powers noted childhood physical or sexual abuse may affect eating patterns in patients with PTSD. “The evidence suggests these types of trauma exposure can be risk factors for the development of an eating disorder.”

Undiagnosed eating pathology may exacerbate functional impairment from PTSD and weaken the impact of evidence-based treatment.

Such patients are challenging to treat as they may not have the requisite skills to fully engage in exposure therapy, an evidence-based approach to treat PTSD, said Mr. Powers.

To determine whether PTSD would be significantly linked to greater eating disorder impairment (EDI) compared with other anxiety-related diagnoses and whether this would impair treatment, investigators studied 748 patients with an anxiety disorder who were attending a cognitive behavioral therapy (CBT) clinic. Anxiety disorders included PTSD, obsessive-compulsive disorder (OCD), social anxiety, and panic disorder.

Participants completed the 16-item Clinical Impairment Assessment (CIA) questionnaire, which includes questions about eating habits and feelings about food, body shape, and weight over the previous 4 weeks. Participants also reported anxiety symptom severity at the beginning, during, and end of treatment.
 

Need for better screening

Results showed that compared with those who had other anxiety disorders, patients with PTSD were three times more likely to have disordered eating (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.47-6.37; P = .003).

In addition, higher baseline CIA scores predicted poorer PTSD treatment outcome (beta = –1.4; 95% CI, –1.67 to –1.10; P < .01).

“Having higher baseline CIA scores meant that patients’ PTSD symptoms did not remit as strongly compared to those with lower scores,” said Mr. Powers.

Patients with both PTSD and an eating disorder may have difficulty with regulating emotions and tolerating distress, he said.

“They may use binge eating, purging, or food restriction as strategies to regulate emotions. These behaviors may allow patients to become numb to or avoid heightened emotions that come from having PTSD and an eating disorder.”

Prior research linked perfectionism tendencies to poorer response to PTSD treatment. Those with an eating disorder may share similar tendencies, said Mr. Powers.

“If someone is consistently thinking negatively about their eating or body to the point where it interrupts their functioning, they may not be as likely to fully engage with PTSD treatment,” he said.

Ideally, clinicians would screen all patients with PTSD for an eating disorder, said Mr. Powers. “If screening instruments aren’t feasible or available, even just inquiring about body image or history of maladaptive eating behaviors can be helpful.”

He added this could open up a conversation about a traumatic event in the patient’s past.
 

Confirmatory research

Commenting on the study, Karen S. Mitchell, PhD, clinical research psychologist, National Center for PTSD, VA Boston Healthcare System, and associate professor in psychiatry, Boston University, said she was “excited” to see this research.

Boston University

“Very few studies have examined the impact of baseline eating disorder symptoms on PTSD treatment outcomes or vice versa,” she said.

The study findings “add to the small but growing body of evidence suggesting that comorbid PTSD and eating disorder symptoms can impact recovery from each disorder,” she said.

She noted the importance of assessing comorbidity in patients presenting for treatment and of addressing comorbidity in both eating disorders and PTSD treatment. “But we need more research on how best to do this.”

Mr. Powers and Dr. Mitchell have reported no relevant financial relationships.
 

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

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

The differences between patients who have PsA with axial involvement (AxPsA) and patients who have axial spondyloarthritis with psoriasis (AxSpA+PsO) continue to remain a strong area of interest. Regierer and colleagues recently compared 359 patients with AxPsA vs 181 patients with AxSpA+PsO. These patients were enrolled into the RABBIT-SpA prospective longitudinal cohort study. Given the lack of definition of AxPsA, two definitions were used: 1) clinical judgment by the rheumatologist and 2) imaging (x-ray or MRI) findings. Regardless of clinical or imaging definition used, compared with patients who have AxSpA+PsO those with AxPsA were significantly more often women, were older, were less often HLA-B27 positive, and had more frequent peripheral manifestations but less frequent uveitis. The two diseases thus have significant differences; these should be carefully considered while making treatment decisions.

Another major research focus is on the influence of sex on PsA treatment response. Eder and colleagues conducted a post hoc analysis of pooled data from phase 3 randomized controlled trials that included 816 patients with PsA who received tofacitinib, adalimumab, or placebo. They demonstrate that at 3 months, tofacitinib was more efficacious than placebo, irrespective of sex. However, a higher proportion of men vs women receiving tofacitinib achieved minimal disease activity. This might be due to baseline differences in disease activity. The American College of Rheumatology 20/50/70 response rates were comparable. The incidence of treatment-emergent adverse events was similar in men and women receiving tofacitinib. Thus, sex significantly influences achieving low disease state. Understanding the mechanisms underlying sex differences will help improve treatment response rates in women with PsA.

Atherosclerotic vascular disease (ASVD) is an important comorbidity of PsA. Predicting ASVD remains difficult. The triglyceride-glucose (TyG) index — calculated as ln[fasting triglycerides (in mg/dL) × fasting glucose (in mg/dL)/2] — was recently identified as a marker of insulin resistance and ASVD. Xie and colleagues conducted a cross-sectional study in 165 patients with PsA who underwent carotid ultrasound and had data available for the TyG index. In a model that was adjusted for age, sex, comorbidities, smoking, BMI, low-density lipoprotein cholesterol, psoriasis area and severity index, and disease activity index for PsA, the TyG index was significantly associated with the presence of carotid atherosclerosis (adjusted odds ratio [aOR] 2.69; 95% CI 1.02-7.11) as well as carotid artery plaque (aOR 3.61; 95% CI 1.15-11.38). Thus, this easily calculated marker is associated with ASVD independent of demographic, traditional risk factors, and disease activity and needs further evaluation in prospective studies.

BOSTON – Atogepant helped reduce the number of mean migraine days among adults with episodic migraine who failed multiple other oral migraine medications, according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.

Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.

Vall d’Hebron University Hospital

The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
 

Results from ELEVATE

Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.

“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”

The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.

The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.

Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*

Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.

That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.

Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
 

‘Exciting that it works well’ in difficult-to-treat patients

Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.

“We needed something that was going to be better than what we had before,” he said.

Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.

He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.

For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.

“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.

Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”

Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.

*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population. 

BOSTON – Atogepant helped reduce the number of mean migraine days among adults with episodic migraine who failed multiple other oral migraine medications, according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.

Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.

Vall d’Hebron University Hospital

The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
 

Results from ELEVATE

Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.

“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”

The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.

The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.

Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*

Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.

That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.

Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
 

‘Exciting that it works well’ in difficult-to-treat patients

Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.

“We needed something that was going to be better than what we had before,” he said.

Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.

He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.

For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.

“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.

Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”

Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.

*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population. 

BOSTON – Atogepant helped reduce the number of mean migraine days among adults with episodic migraine who failed multiple other oral migraine medications, according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.

Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.

Vall d’Hebron University Hospital

The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
 

Results from ELEVATE

Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.

“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”

The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.

The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.

Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*

Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.

That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.

Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
 

‘Exciting that it works well’ in difficult-to-treat patients

Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.

“We needed something that was going to be better than what we had before,” he said.

Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.

He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.

For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.

“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.

Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”

Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.

*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population. 

Serrano and colleagues performed a multicenter, double-blind, phase 2b randomized trial investigating various dosing schedules of exemestane (25 mg once daily, three times weekly, or once weekly) for 4-6 weeks before surgery, among 180 postmenopausal women with stage 0-II estrogen receptor–positive breast cancer (BC). Among adherent patients (89% of the population), 25 mg exemestane given three times weekly was noninferior to once-daily dosing in reducing serum estradiol (mean decrease of estradiol, -92% and -91%, respectively; difference in percentage change, 2.0%; P for noninferiority = .02), whereas once-weekly dosing was less effective. Adverse effects were similar, although owing to short exposure in this study, it will be important to explore longer-term differences because aromatase inhibitor–related toxicities may arise later on. These data support further exploration of alternative endocrine therapy schedules in the prevention setting, and also in adjuvant treatment for women who are unable to tolerate the standard dose.

Screening mammography reduces mortality from BC, and advances in techniques, such as digital breast tomosynthesis (DBT), have led to lower recall rates, and higher cancer detection rates compared with digital mammography (DM). Additionally, DBT has demonstrated better cancer detection compared with DM, notably among younger women and those with dense breast tissue.² A retrospective study including over 2.5 million screening mammograms among women 40-79 years of age showed that, compared with DM, DBT had a lower recall rate (10.3% vs 8.9%; adjusted odds ratio [OR] 0.92; P < .001) and higher positive predictive value of recall (4.3% vs 5.9%; adjusted OR 1.33; P < .001), cancer detection rate (4.5 of 1000 vs 5.3 of 1000 screening mammograms; adjusted OR 1.24; P < .001), and biopsy rate (17.6 of 1000 vs 14.5 of 1000 screening mammograms; adjusted OR 1.33, P < .001) (Conant et al). These data add to the growing body of evidence showing superiority in BC screening with DBT vs DM and add support of this technique in routine clinical practice for our patients.

The initial treatment strategy for metastatic hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) BC involves endocrine therapy in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor. The three PALOMA trials demonstrated progression-free survival (PFS) benefit with palbociclib plus endocrine therapy, and a pooled analysis of these studies reported consistent improvement in PFS with palbociclib plus endocrine therapy vs endocrine therapy alone in older patients.³ A retrospective study evaluated real-world outcomes of palbociclib plus letrozole vs letrozole alone among 796 women ≥ 65 years of age with HR+/HER- metastatic BC. First-line palbociclib plus letrozole compared with letrozole alone significantly improved median real-world PFS (22.2 vs 15.8 months; adjusted hazard ratio [HR] 0.59; P < .001) and overall survival (not reached vs 43.4 months; adjusted HR 0.55; P < .001). Real-world best tumor response rate was also higher (52.4% vs 22.1%; OR 2.0; P < .001) (Rugo et al). This study highlights the effectiveness of palbociclib plus letrozole in older adults with HR+/HER2- metastatic BC and the benefits of examining a real-world population that adds value to the existing data from randomized clinical trials.

Additional References

1. De Censi A, Lazzeroni M, Puntoni M, et al. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas. Abstract GS4-08. https://www.sabcs.org/Portals/SABCS2016/2022%20SABCS/Friday.pdf?ver=2022-11-22-205358-350
2. Conant EF, Barlow WE, Herschorn SD, et al; Population-based Research Optimizing Screening Through Personalized Regimen (PROSPR) Consortium. Association of digital breast tomosynthesis vs digital mammography with cancer detection and recall rates by age and breast density. JAMA Oncol. 2019;5:635-64 doi: 10.1001/jamaoncol.2018.7078
3. Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123-13 doi: 10.1016/j.ejca.2018.05.017

Serrano and colleagues performed a multicenter, double-blind, phase 2b randomized trial investigating various dosing schedules of exemestane (25 mg once daily, three times weekly, or once weekly) for 4-6 weeks before surgery, among 180 postmenopausal women with stage 0-II estrogen receptor–positive breast cancer (BC). Among adherent patients (89% of the population), 25 mg exemestane given three times weekly was noninferior to once-daily dosing in reducing serum estradiol (mean decrease of estradiol, -92% and -91%, respectively; difference in percentage change, 2.0%; P for noninferiority = .02), whereas once-weekly dosing was less effective. Adverse effects were similar, although owing to short exposure in this study, it will be important to explore longer-term differences because aromatase inhibitor–related toxicities may arise later on. These data support further exploration of alternative endocrine therapy schedules in the prevention setting, and also in adjuvant treatment for women who are unable to tolerate the standard dose.

Screening mammography reduces mortality from BC, and advances in techniques, such as digital breast tomosynthesis (DBT), have led to lower recall rates, and higher cancer detection rates compared with digital mammography (DM). Additionally, DBT has demonstrated better cancer detection compared with DM, notably among younger women and those with dense breast tissue.² A retrospective study including over 2.5 million screening mammograms among women 40-79 years of age showed that, compared with DM, DBT had a lower recall rate (10.3% vs 8.9%; adjusted odds ratio [OR] 0.92; P < .001) and higher positive predictive value of recall (4.3% vs 5.9%; adjusted OR 1.33; P < .001), cancer detection rate (4.5 of 1000 vs 5.3 of 1000 screening mammograms; adjusted OR 1.24; P < .001), and biopsy rate (17.6 of 1000 vs 14.5 of 1000 screening mammograms; adjusted OR 1.33, P < .001) (Conant et al). These data add to the growing body of evidence showing superiority in BC screening with DBT vs DM and add support of this technique in routine clinical practice for our patients.

The initial treatment strategy for metastatic hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) BC involves endocrine therapy in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor. The three PALOMA trials demonstrated progression-free survival (PFS) benefit with palbociclib plus endocrine therapy, and a pooled analysis of these studies reported consistent improvement in PFS with palbociclib plus endocrine therapy vs endocrine therapy alone in older patients.³ A retrospective study evaluated real-world outcomes of palbociclib plus letrozole vs letrozole alone among 796 women ≥ 65 years of age with HR+/HER- metastatic BC. First-line palbociclib plus letrozole compared with letrozole alone significantly improved median real-world PFS (22.2 vs 15.8 months; adjusted hazard ratio [HR] 0.59; P < .001) and overall survival (not reached vs 43.4 months; adjusted HR 0.55; P < .001). Real-world best tumor response rate was also higher (52.4% vs 22.1%; OR 2.0; P < .001) (Rugo et al). This study highlights the effectiveness of palbociclib plus letrozole in older adults with HR+/HER2- metastatic BC and the benefits of examining a real-world population that adds value to the existing data from randomized clinical trials.

Additional References

1. De Censi A, Lazzeroni M, Puntoni M, et al. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas. Abstract GS4-08. https://www.sabcs.org/Portals/SABCS2016/2022%20SABCS/Friday.pdf?ver=2022-11-22-205358-350
2. Conant EF, Barlow WE, Herschorn SD, et al; Population-based Research Optimizing Screening Through Personalized Regimen (PROSPR) Consortium. Association of digital breast tomosynthesis vs digital mammography with cancer detection and recall rates by age and breast density. JAMA Oncol. 2019;5:635-64 doi: 10.1001/jamaoncol.2018.7078
3. Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123-13 doi: 10.1016/j.ejca.2018.05.017

Serrano and colleagues performed a multicenter, double-blind, phase 2b randomized trial investigating various dosing schedules of exemestane (25 mg once daily, three times weekly, or once weekly) for 4-6 weeks before surgery, among 180 postmenopausal women with stage 0-II estrogen receptor–positive breast cancer (BC). Among adherent patients (89% of the population), 25 mg exemestane given three times weekly was noninferior to once-daily dosing in reducing serum estradiol (mean decrease of estradiol, -92% and -91%, respectively; difference in percentage change, 2.0%; P for noninferiority = .02), whereas once-weekly dosing was less effective. Adverse effects were similar, although owing to short exposure in this study, it will be important to explore longer-term differences because aromatase inhibitor–related toxicities may arise later on. These data support further exploration of alternative endocrine therapy schedules in the prevention setting, and also in adjuvant treatment for women who are unable to tolerate the standard dose.

Screening mammography reduces mortality from BC, and advances in techniques, such as digital breast tomosynthesis (DBT), have led to lower recall rates, and higher cancer detection rates compared with digital mammography (DM). Additionally, DBT has demonstrated better cancer detection compared with DM, notably among younger women and those with dense breast tissue.² A retrospective study including over 2.5 million screening mammograms among women 40-79 years of age showed that, compared with DM, DBT had a lower recall rate (10.3% vs 8.9%; adjusted odds ratio [OR] 0.92; P < .001) and higher positive predictive value of recall (4.3% vs 5.9%; adjusted OR 1.33; P < .001), cancer detection rate (4.5 of 1000 vs 5.3 of 1000 screening mammograms; adjusted OR 1.24; P < .001), and biopsy rate (17.6 of 1000 vs 14.5 of 1000 screening mammograms; adjusted OR 1.33, P < .001) (Conant et al). These data add to the growing body of evidence showing superiority in BC screening with DBT vs DM and add support of this technique in routine clinical practice for our patients.

The initial treatment strategy for metastatic hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) BC involves endocrine therapy in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor. The three PALOMA trials demonstrated progression-free survival (PFS) benefit with palbociclib plus endocrine therapy, and a pooled analysis of these studies reported consistent improvement in PFS with palbociclib plus endocrine therapy vs endocrine therapy alone in older patients.³ A retrospective study evaluated real-world outcomes of palbociclib plus letrozole vs letrozole alone among 796 women ≥ 65 years of age with HR+/HER- metastatic BC. First-line palbociclib plus letrozole compared with letrozole alone significantly improved median real-world PFS (22.2 vs 15.8 months; adjusted hazard ratio [HR] 0.59; P < .001) and overall survival (not reached vs 43.4 months; adjusted HR 0.55; P < .001). Real-world best tumor response rate was also higher (52.4% vs 22.1%; OR 2.0; P < .001) (Rugo et al). This study highlights the effectiveness of palbociclib plus letrozole in older adults with HR+/HER2- metastatic BC and the benefits of examining a real-world population that adds value to the existing data from randomized clinical trials.

Additional References

1. De Censi A, Lazzeroni M, Puntoni M, et al. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas. Abstract GS4-08. https://www.sabcs.org/Portals/SABCS2016/2022%20SABCS/Friday.pdf?ver=2022-11-22-205358-350
2. Conant EF, Barlow WE, Herschorn SD, et al; Population-based Research Optimizing Screening Through Personalized Regimen (PROSPR) Consortium. Association of digital breast tomosynthesis vs digital mammography with cancer detection and recall rates by age and breast density. JAMA Oncol. 2019;5:635-64 doi: 10.1001/jamaoncol.2018.7078
3. Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123-13 doi: 10.1016/j.ejca.2018.05.017

Torrelo and colleagues described the efficacy and safety of baricitinib in combination with topical corticosteroids in pediatric patients with moderate to severe atopic dermatitis. At the high dose of 4 mg daily, the IGA success rate was about 40%, similar to what we expect for adults treated with dupilumab and less than what we might expect with upadacitinib.

Studies have already been done on efficacy and safety of baricitinib in adults with atopic dermatitis. But baricitinib is indicated for the treatment of adult patients with severe alopecia areata and is not currently indicated as a treatment for anyone with atopic dermatitis, at least not in the United States. At this time, I think the most useful aspect of Torrelo and colleagues' findings is being able to tell our adult patients with alopecia areata that baricitinib was safe enough that they could test it in children as young as 2 years old with eczema.

Perälä and colleagues' report comparing topical tacrolimus and topical corticosteroids (1% hydrocortisone acetate or, if needed, 0.1% hydrocortisone butyrate ointment) in young children with atopic dermatitis is fascinating. They saw patients back at 1 week and followed them for 3 years. In just 1 week, both groups had massive and similar improvement in their atopic dermatitis, and that improvement continued throughout the study. Here are some take-home points:

• Atopic dermatitis responds rapidly to low-to-medium–strength topical steroids.
• Bringing patients back at 1 week may have been a critical aspect of this study, as adherence to topicals can be abysmal; bringing patients back at 1 week probably enables them to use their treatment much better than they would otherwise.
• If we need a nonsteroidal topical, we have an excellent one available at low cost in the form of topical tacrolimus.

Perälä and colleagues also did this study to see whether good treatment of atopic dermatitis in these young children would have long-term benefits on atopic airway issues. Because the researchers didn't have a placebo group (and considered it unethical to have one), we cannot tell whether the topical treatment provided any benefit in that regard.

Yamamoto-Hanada and colleaguesexamined whether "enhanced" topical steroid treatment would prevent food allergy in children with eczema compared with standard topical steroid treatment. Perhaps a better word than "enhanced" would be "aggressive." The enhanced treatment entailed having infants receive alclometasone dipropionate for the whole face and betamethasone valerate for the whole body except face and scalp. While the researchers saw a reduction in egg allergy (from roughly 40% to 30%), they also saw reduced body weight and height. A key take-home message is that with extensive use of topical steroids, we can see systemic effects.

Torrelo and colleagues described the efficacy and safety of baricitinib in combination with topical corticosteroids in pediatric patients with moderate to severe atopic dermatitis. At the high dose of 4 mg daily, the IGA success rate was about 40%, similar to what we expect for adults treated with dupilumab and less than what we might expect with upadacitinib.

Studies have already been done on efficacy and safety of baricitinib in adults with atopic dermatitis. But baricitinib is indicated for the treatment of adult patients with severe alopecia areata and is not currently indicated as a treatment for anyone with atopic dermatitis, at least not in the United States. At this time, I think the most useful aspect of Torrelo and colleagues' findings is being able to tell our adult patients with alopecia areata that baricitinib was safe enough that they could test it in children as young as 2 years old with eczema.

Perälä and colleagues' report comparing topical tacrolimus and topical corticosteroids (1% hydrocortisone acetate or, if needed, 0.1% hydrocortisone butyrate ointment) in young children with atopic dermatitis is fascinating. They saw patients back at 1 week and followed them for 3 years. In just 1 week, both groups had massive and similar improvement in their atopic dermatitis, and that improvement continued throughout the study. Here are some take-home points:

• Atopic dermatitis responds rapidly to low-to-medium–strength topical steroids.
• Bringing patients back at 1 week may have been a critical aspect of this study, as adherence to topicals can be abysmal; bringing patients back at 1 week probably enables them to use their treatment much better than they would otherwise.
• If we need a nonsteroidal topical, we have an excellent one available at low cost in the form of topical tacrolimus.

Perälä and colleagues also did this study to see whether good treatment of atopic dermatitis in these young children would have long-term benefits on atopic airway issues. Because the researchers didn't have a placebo group (and considered it unethical to have one), we cannot tell whether the topical treatment provided any benefit in that regard.

Yamamoto-Hanada and colleaguesexamined whether "enhanced" topical steroid treatment would prevent food allergy in children with eczema compared with standard topical steroid treatment. Perhaps a better word than "enhanced" would be "aggressive." The enhanced treatment entailed having infants receive alclometasone dipropionate for the whole face and betamethasone valerate for the whole body except face and scalp. While the researchers saw a reduction in egg allergy (from roughly 40% to 30%), they also saw reduced body weight and height. A key take-home message is that with extensive use of topical steroids, we can see systemic effects.

Torrelo and colleagues described the efficacy and safety of baricitinib in combination with topical corticosteroids in pediatric patients with moderate to severe atopic dermatitis. At the high dose of 4 mg daily, the IGA success rate was about 40%, similar to what we expect for adults treated with dupilumab and less than what we might expect with upadacitinib.

Studies have already been done on efficacy and safety of baricitinib in adults with atopic dermatitis. But baricitinib is indicated for the treatment of adult patients with severe alopecia areata and is not currently indicated as a treatment for anyone with atopic dermatitis, at least not in the United States. At this time, I think the most useful aspect of Torrelo and colleagues' findings is being able to tell our adult patients with alopecia areata that baricitinib was safe enough that they could test it in children as young as 2 years old with eczema.

Perälä and colleagues' report comparing topical tacrolimus and topical corticosteroids (1% hydrocortisone acetate or, if needed, 0.1% hydrocortisone butyrate ointment) in young children with atopic dermatitis is fascinating. They saw patients back at 1 week and followed them for 3 years. In just 1 week, both groups had massive and similar improvement in their atopic dermatitis, and that improvement continued throughout the study. Here are some take-home points:

• Atopic dermatitis responds rapidly to low-to-medium–strength topical steroids.
• Bringing patients back at 1 week may have been a critical aspect of this study, as adherence to topicals can be abysmal; bringing patients back at 1 week probably enables them to use their treatment much better than they would otherwise.
• If we need a nonsteroidal topical, we have an excellent one available at low cost in the form of topical tacrolimus.

Perälä and colleagues also did this study to see whether good treatment of atopic dermatitis in these young children would have long-term benefits on atopic airway issues. Because the researchers didn't have a placebo group (and considered it unethical to have one), we cannot tell whether the topical treatment provided any benefit in that regard.

Yamamoto-Hanada and colleaguesexamined whether "enhanced" topical steroid treatment would prevent food allergy in children with eczema compared with standard topical steroid treatment. Perhaps a better word than "enhanced" would be "aggressive." The enhanced treatment entailed having infants receive alclometasone dipropionate for the whole face and betamethasone valerate for the whole body except face and scalp. While the researchers saw a reduction in egg allergy (from roughly 40% to 30%), they also saw reduced body weight and height. A key take-home message is that with extensive use of topical steroids, we can see systemic effects.