To the Editor:

Oral immunosuppressive therapies are prescribed for moderate to severe atopic dermatitis. Patients often consult YouTube to make informed decisions about these therapies. In the United States, most health-related online searches are initiated through a search engine, which frequently leads to social media sites such as YouTube. Recent studies have examined the reasons why users turn to the Internet for health-related information, indicating that users typically seek specific information regarding health concerns.^1,2 Furthermore, social media platforms such as YouTube are a popular means of sharing health information with the public.^3-5 Currently, YouTube has more than 1 billion registered users, and 30 million health-related videos are watched each day.⁶ Almost one-third of US consumers use YouTube, Facebook, and Twitter to obtain medical information.⁷ YouTube is a versatile tool because of its video-discovery mechanisms such as a keyword-based search engine, video-recommendation system, highlight feature for videos on home pages, and the capacity to embed YouTube videos on various web pages.⁸ Searchers use videos that are short, fast paced, emotion evoking, from credible sources, recently uploaded, and relevant to the searcher for aiding in health decisions.⁹ Furthermore, studies have demonstrated YouTube’s capacity to support a change in attitude and increase users’ knowledge. In fact, YouTube had higher impact on recall, attitudes, and behaviors when compared with written materials on other social media platforms, such as Facebook and Twitter.⁹ We conducted a cross-sectional study to examine the quality of YouTube videos on oral therapies for atopic dermatitis, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil.

On April 23, 2020, we performed 8 searches using a private browser with default filters on YouTube (Figure). Injectables were not included in the analysis, as the YouTube experience on dupilumab previously has been investigated.¹⁰ The top 40 videos from each search were screened by 3 researchers. Duplicates, non–English-language videos, and videos that did not discuss atopic dermatitis or oral therapies were excluded, resulting in 73 videos included in this analysis. Testimonials generated by patients made up 39 of 73 (53.4%) videos. Health care professionals created 23 of 73 (31.5%) videos, and educators with financial interest created 11 of 73 (15.1%) videos. The dates of production for the videos spanned from 2008 to 2020.

Importantly, this analysis is limited by its lack of quality-assessment tools for video-based resources such as JAMA score and DISCERN score.^14,15 However, these metrics have limited ability to evaluate audiovisual elements, indicating the need for novel tools to score their validity.

To the Editor:

Oral immunosuppressive therapies are prescribed for moderate to severe atopic dermatitis. Patients often consult YouTube to make informed decisions about these therapies. In the United States, most health-related online searches are initiated through a search engine, which frequently leads to social media sites such as YouTube. Recent studies have examined the reasons why users turn to the Internet for health-related information, indicating that users typically seek specific information regarding health concerns.^1,2 Furthermore, social media platforms such as YouTube are a popular means of sharing health information with the public.^3-5 Currently, YouTube has more than 1 billion registered users, and 30 million health-related videos are watched each day.⁶ Almost one-third of US consumers use YouTube, Facebook, and Twitter to obtain medical information.⁷ YouTube is a versatile tool because of its video-discovery mechanisms such as a keyword-based search engine, video-recommendation system, highlight feature for videos on home pages, and the capacity to embed YouTube videos on various web pages.⁸ Searchers use videos that are short, fast paced, emotion evoking, from credible sources, recently uploaded, and relevant to the searcher for aiding in health decisions.⁹ Furthermore, studies have demonstrated YouTube’s capacity to support a change in attitude and increase users’ knowledge. In fact, YouTube had higher impact on recall, attitudes, and behaviors when compared with written materials on other social media platforms, such as Facebook and Twitter.⁹ We conducted a cross-sectional study to examine the quality of YouTube videos on oral therapies for atopic dermatitis, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil.

On April 23, 2020, we performed 8 searches using a private browser with default filters on YouTube (Figure). Injectables were not included in the analysis, as the YouTube experience on dupilumab previously has been investigated.¹⁰ The top 40 videos from each search were screened by 3 researchers. Duplicates, non–English-language videos, and videos that did not discuss atopic dermatitis or oral therapies were excluded, resulting in 73 videos included in this analysis. Testimonials generated by patients made up 39 of 73 (53.4%) videos. Health care professionals created 23 of 73 (31.5%) videos, and educators with financial interest created 11 of 73 (15.1%) videos. The dates of production for the videos spanned from 2008 to 2020.

Importantly, this analysis is limited by its lack of quality-assessment tools for video-based resources such as JAMA score and DISCERN score.^14,15 However, these metrics have limited ability to evaluate audiovisual elements, indicating the need for novel tools to score their validity.

To the Editor:

Oral immunosuppressive therapies are prescribed for moderate to severe atopic dermatitis. Patients often consult YouTube to make informed decisions about these therapies. In the United States, most health-related online searches are initiated through a search engine, which frequently leads to social media sites such as YouTube. Recent studies have examined the reasons why users turn to the Internet for health-related information, indicating that users typically seek specific information regarding health concerns.^1,2 Furthermore, social media platforms such as YouTube are a popular means of sharing health information with the public.^3-5 Currently, YouTube has more than 1 billion registered users, and 30 million health-related videos are watched each day.⁶ Almost one-third of US consumers use YouTube, Facebook, and Twitter to obtain medical information.⁷ YouTube is a versatile tool because of its video-discovery mechanisms such as a keyword-based search engine, video-recommendation system, highlight feature for videos on home pages, and the capacity to embed YouTube videos on various web pages.⁸ Searchers use videos that are short, fast paced, emotion evoking, from credible sources, recently uploaded, and relevant to the searcher for aiding in health decisions.⁹ Furthermore, studies have demonstrated YouTube’s capacity to support a change in attitude and increase users’ knowledge. In fact, YouTube had higher impact on recall, attitudes, and behaviors when compared with written materials on other social media platforms, such as Facebook and Twitter.⁹ We conducted a cross-sectional study to examine the quality of YouTube videos on oral therapies for atopic dermatitis, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil.

On April 23, 2020, we performed 8 searches using a private browser with default filters on YouTube (Figure). Injectables were not included in the analysis, as the YouTube experience on dupilumab previously has been investigated.¹⁰ The top 40 videos from each search were screened by 3 researchers. Duplicates, non–English-language videos, and videos that did not discuss atopic dermatitis or oral therapies were excluded, resulting in 73 videos included in this analysis. Testimonials generated by patients made up 39 of 73 (53.4%) videos. Health care professionals created 23 of 73 (31.5%) videos, and educators with financial interest created 11 of 73 (15.1%) videos. The dates of production for the videos spanned from 2008 to 2020.

Importantly, this analysis is limited by its lack of quality-assessment tools for video-based resources such as JAMA score and DISCERN score.^14,15 However, these metrics have limited ability to evaluate audiovisual elements, indicating the need for novel tools to score their validity.

To the Editor:

Atopic dermatitis (eczema) affects approximately 20% of children worldwide.¹ In atopic dermatitis management, patient education is crucial for optimal outcomes.² The COVID-19 pandemic has impacted patient-physician interactions. To ensure safety of patients and physicians, visits may have been canceled, postponed, or conducted virtually, leaving less time for discussion and questions.³ As a consequence, patients may seek information about atopic dermatitis from alternative sources, including YouTube videos. We performed a cross-sectional study to analyze YouTube videos about topical treatments for atopic dermatitis.

During the week of July 16, 2020, we performed 4 private browser YouTube searches with default filters using the following terms: eczema topicals, eczema topical treatments, atopic dermatitis topicals, and atopic dermatitis topical treatments. For video selection, we defined topical treatments as topical corticosteroids, topical calcineurin inhibitors, crisaborole, emollients, wet wraps, and any prospective treatment topically administered. For each of the 4 searches, 2 researchers (A.M. and A.T.) independently examined the top 75 videos, yielding a total of 300 videos. Of them, 98 videos were duplicates, 19 videos were not about atopic dermatitis, and 91 videos were not about topical treatments, leaving a total of 92 videos for analysis (Figure 1).

Although less popular, professional source videos had a significantly higher DISCERN overall quality rating score (question 16) compared to those categorized as nonprofessional source (3.92 vs 1.53; P<.001). In contrast, nonprofessional source videos scored significantly higher on the quality-of-life question (question 13) compared to professional source videos (3.90 vs 2.56; P<.001)(eTable). (Three professional source videos were removed from YouTube before DISCERN scores could be assigned.)

To the Editor:

Atopic dermatitis (eczema) affects approximately 20% of children worldwide.¹ In atopic dermatitis management, patient education is crucial for optimal outcomes.² The COVID-19 pandemic has impacted patient-physician interactions. To ensure safety of patients and physicians, visits may have been canceled, postponed, or conducted virtually, leaving less time for discussion and questions.³ As a consequence, patients may seek information about atopic dermatitis from alternative sources, including YouTube videos. We performed a cross-sectional study to analyze YouTube videos about topical treatments for atopic dermatitis.

During the week of July 16, 2020, we performed 4 private browser YouTube searches with default filters using the following terms: eczema topicals, eczema topical treatments, atopic dermatitis topicals, and atopic dermatitis topical treatments. For video selection, we defined topical treatments as topical corticosteroids, topical calcineurin inhibitors, crisaborole, emollients, wet wraps, and any prospective treatment topically administered. For each of the 4 searches, 2 researchers (A.M. and A.T.) independently examined the top 75 videos, yielding a total of 300 videos. Of them, 98 videos were duplicates, 19 videos were not about atopic dermatitis, and 91 videos were not about topical treatments, leaving a total of 92 videos for analysis (Figure 1).

Although less popular, professional source videos had a significantly higher DISCERN overall quality rating score (question 16) compared to those categorized as nonprofessional source (3.92 vs 1.53; P<.001). In contrast, nonprofessional source videos scored significantly higher on the quality-of-life question (question 13) compared to professional source videos (3.90 vs 2.56; P<.001)(eTable). (Three professional source videos were removed from YouTube before DISCERN scores could be assigned.)

To the Editor:

Atopic dermatitis (eczema) affects approximately 20% of children worldwide.¹ In atopic dermatitis management, patient education is crucial for optimal outcomes.² The COVID-19 pandemic has impacted patient-physician interactions. To ensure safety of patients and physicians, visits may have been canceled, postponed, or conducted virtually, leaving less time for discussion and questions.³ As a consequence, patients may seek information about atopic dermatitis from alternative sources, including YouTube videos. We performed a cross-sectional study to analyze YouTube videos about topical treatments for atopic dermatitis.

During the week of July 16, 2020, we performed 4 private browser YouTube searches with default filters using the following terms: eczema topicals, eczema topical treatments, atopic dermatitis topicals, and atopic dermatitis topical treatments. For video selection, we defined topical treatments as topical corticosteroids, topical calcineurin inhibitors, crisaborole, emollients, wet wraps, and any prospective treatment topically administered. For each of the 4 searches, 2 researchers (A.M. and A.T.) independently examined the top 75 videos, yielding a total of 300 videos. Of them, 98 videos were duplicates, 19 videos were not about atopic dermatitis, and 91 videos were not about topical treatments, leaving a total of 92 videos for analysis (Figure 1).

Although less popular, professional source videos had a significantly higher DISCERN overall quality rating score (question 16) compared to those categorized as nonprofessional source (3.92 vs 1.53; P<.001). In contrast, nonprofessional source videos scored significantly higher on the quality-of-life question (question 13) compared to professional source videos (3.90 vs 2.56; P<.001)(eTable). (Three professional source videos were removed from YouTube before DISCERN scores could be assigned.)

Plants can contribute to a variety of dermatoses. The Toxicodendron genus, which includes poison ivy, poison oak, and poison sumac, is a well-known and common cause of allergic contact dermatitis (ACD), but many other plants can cause direct or airborne contact dermatitis, especially in gardeners, florists, and farmers. This article provides an overview of different plant-related dermatoses and culprit plants as well as how these dermatoses should be diagnosed and treated.

Epidemiology

Plant dermatoses affect more than 50 million individuals each year.^1,2 In the United States, the Toxicodendron genus causes ACD in more than 70% of exposed individuals, leading to medical visits.³ An urgent care visit for a plant-related dermatitis is estimated to cost $168, while an emergency department visit can cost 3 times as much.⁴ Although less common, Compositae plants are another important culprit of plant dermatitis, particularly in gardeners, florists, and farmers. Data from the 2017-2018 North American Contact Dermatitis Group screening series (N=4947) showed sesquiterpene lactones and Compositae to be positive in 0.5% of patch-tested patients.⁵

Plant Dermatitis Classifications

Plant dermatitis can be classified into 5 main categories: ACD, mechanical irritant contact dermatitis, chemical irritant contact dermatitis, light-mediated dermatitis, and pseudophytodermatitis.⁶

Allergic contact dermatitis is an immune-mediated type IV delayed hypersensitivity reaction. The common molecular allergens in plants include phenols, α-methylene-γ-butyrolactones, quinones, terpenes, disulfides, isothiocyanates, and polyacetylenic derivatives.⁶

Plant contact dermatitis due to mechanical and chemical irritants is precipitated by multiple mechanisms, including disruption of the epidermal barrier and subsequent cytokine release from keratinocytes.⁷ Nonimmunologic contact urticaria from plants is thought to be a type of irritant reaction precipitated by mechanical or chemical trauma.⁸

Light-mediated dermatitis includes phytophotodermatitis and photoallergic contact dermatitis. Phytophotodermatitis is a phototoxic reaction triggered by exposure to both plant-derived furanocoumarin and UVA light.⁹ By contrast, photoallergic contact dermatitis is a delayed hypersensitivity reaction from prior sensitization to a light-activated antigen.¹⁰

Pseudophytodermatitis, as its name implies, is not truly mediated by an allergen or irritant intrinsic to the plant but rather by dyes, waxes, insecticides, or arthropods that inhabit the plant or are secondarily applied.⁶

Common Plant Allergens

Anacardiaceae Family
Most of the allergenic plants within the Anacardiaceae family belong to the Toxicodendron genus, which encompasses poison ivy (Toxicodendron radicans), poison oak (Toxicodendron pubescens,Toxicodendron quercifolium, Toxicodendron diversiloum), and poison sumac (Toxicodendron vernix). Poison ivy is the celebrity of the Anacardiaceae family and contributes to most cases of plant-related ACD. It is found in every state in the continental United States. Poison oak is another common culprit found in the western and southeastern United States.¹¹ Plants within the Anacardiaceae family contain an oleoresin called urushiol, which is the primary sensitizing substance. Although poison ivy and poison oak grow well in full sun to partial shade, poison sumac typically is found in damp swampy areas east of the Rocky Mountains. Most cases of ACD related to Anacardiaceae species are due to direct contact with urushiol from a Toxicodendron plant, but burning of brush containing Toxicodendron can cause airborne exposure when urushiol oil is carried by smoke particles.¹² Sensitization to Toxicodendron can cause ACD to other Anacardiaceae species such as the Japanese lacquer tree (Toxicodendron vernicifluum), mango tree (Mangifera indica), cashew tree (Anacardium occidentale), and Indian marking nut tree (Semecarpus anacardium).⁶ Cross-reactions to components of the ginkgo tree (Ginkgo biloba) also are possible.

Toxicodendron plants can be more easily identified and avoided with knowledge of their characteristic leaf patterns. The most dependable way to identify poison ivy and poison oak species is to look for plants with 3 leaves, giving rise to the common saying, “Leaves of three, leave them be.” Poison sumac plants have groups of 7 to 13 leaves arranged as pairs along a central rib. Another helpful finding is a black deposit that Toxicodendron species leave behind following trauma to the leaves. Urushiol oxidizes when exposed to air and turns into a black deposit that can be seen on damaged leaves themselves or can be demonstrated in a black spot test to verify if a plant is a Toxicodendron species. The test is performed by gathering (carefully, without direct contact) a few leaves in a paper towel and crushing them to release sap. Within minutes, the sap will turn black if the plant is indeed a Toxicodendron species.¹³Pruritic, edematous, erythematous papules, plaques, and eventual vesicles in a linear distribution are suspicious for Toxicodendron exposure. Although your pet will not develop Toxicodendron ACD, oleoresin-contaminated pets can transfer the oils to their owners after coming into contact with these plants. Toxicodendron dermatitis also can be acquired from oleoresin-contaminated fomites such as clothing and shoes worn in the garden or when hiking. Toxicodendron dermatitis can appear at different sites on the body at different times depending on the amount of oleoresin exposure as well as epidermal thickness. For example, the oleoresin can be transferred from the hands to body areas with a thinner stratum corneum (eg, genitalia) and cause subsequent dermatitis.¹

Compositae Family
The Compositae family (also known as Asteraceae) is a large plant family with more than 20,000 species, including numerous weeds, wildflowers, and vegetables. The flowers, leaves, stems, and pollens of the Compositae family are coated by cyclic esters called sesquiterpene lactones. Mitchell and Dupuis¹⁴ showed that sesquiterpene lactones are the allergens responsible for ACD to various Compositae plants, including ragweed (Ambrosia), sneezeweed (Helenium), and chrysanthemums (Chrysanthemum). Common Compositae vegetables such as lettuce (Lactuca sativa) have been reported to cause ACD in chefs, grocery store produce handlers, gardeners, and even owners of lettuce-eating pet guinea pigs and turtles.¹⁵ Similarly, artichokes (Cynara scolymus) can cause ACD in gardeners.¹⁶ Exposure to Compositae species also has been implicated in photoallergic reactions, and studies have demonstrated that some patients with chronic actinic dermatitis also have positive patch test reactions to Compositae species and/or sesquiterpene lactones.^17,18

In addition to direct contact with Compositae plants, airborne exposure to sesquiterpene lactones can cause ACD.¹⁴ The pattern of airborne contact dermatitis typically involves exposed areas such as the eyelids, central face, and/or neck. The beak sign also can be a clue to airborne contact dermatitis, which involves dermatitis of the face that spares the nasal tip and/or nasal ridge. It is thought that the beak sign may result from increased sebaceous gland concentration on the nose, which prevents penetration of allergens and irritants.¹⁹ Unlike photoallergic contact dermatitis, which also can involve the face, airborne ACD frequently involves photoprotected areas such as the submandibular chin and the upper lip. Davies and Kersey²⁰ reported the case of a groundsman who was cutting grass with dandelions (Taraxacum officinale) and was found to have associated airborne ACD of the face, neck, and forearms due to Compositae allergy. In a different setting, the aromas of chamomile (Matricaria chamomilla) have been reported to cause airborne ACD in a tea drinker.²¹ Paulsen²² found that ingestion of chamomile tea can induce systemic ACD in sensitized individuals.

Alstroemeriaceae, Liliaceae, and Primulaceae
Florists are exposed to many plant species and have a high prevalence of ACD. Thiboutot et al²³ found that 15 of 57 (26%) floral workers experienced hand dermatitis that cleared with time away from work. The Peruvian lily (Alstroemeria, Alstroemeriaceae family), which contains tuliposide A, was found to be the leading cause of sensitization.²³ Tulips (Tulipa, Liliaceae family), as the flower name suggests, also contain tuliposide A, which along with mechanical irritation from the course tecta fibers on the bulbs lead to a dermatitis known as tulip fingers.^24,25 Poison primrose (Primula obconica, Primulaceae family), cultivated for its highly colorful flowers, contains the contact allergen primin.⁶ A common clinical presentation of ACD for any of these culprit flowers is localized dermatitis of the thumb and index finger in a florist or gardener.

Plants That Cause Irritant Reactions

Cactuses
Although the long spines of the Cactaceae family of cactuses is a warning for passersby, it is the small and nearly invisible barbed hairs (glochids) that inflict a more dramatic cutaneous reaction. The prickly pear cactus (Opuntia species) is a good example of such a plant, as its glochids cause mechanical irritation but also can become embedded in the skin and result in subcutaneous granulomas known as sabra dermatitis.²⁶

Stinging Nettle
The dermatologic term urticaria owes its namesake to the stinging nettle plant, which comes from the family Urticaceae. The stinging nettle has small hairs on its leaves, referred to as stinging trichomes, which have needlelike tips that pierce the skin and inject a mix of histamine, formic acid, and acetylcholine, causing a pruritic dermatitis that may last up to 12 hours.²⁷ The plant is found worldwide and is a common weed in North America.

Phytophotodermatitis

Lemons and limes (Rutaceae family) are common culprits of phytophotodermatitis, often causing what is known as a margarita burn after outdoor consumption or preparation of this tasty citrus beverage.²⁸ An accidental spray of lime juice on the skin while adding it to a beer, guacamole, salsa, or any other food or beverage also can cause phytophotodermatitis.^29-31 Although the juice of lemons and limes contains psoralens, the rind can contain a 6- to 186-fold increased concentration.³² Psoralen is the photoactive agent in Rutaceae plants that intercalates in double-stranded DNA and promotes intrastrand cross-links when exposed to UVA light, which ultimately leads to dermatitis.⁹ Phytophotodermatitis commonly causes erythema, edema, and painful bullae on sun-exposed areas and classically heals with hyperpigmentation.

Pseudophytodermatitis can occur in grain farmers and harvesters who handle wheat and/or barley and incidentally come in contact with insects and chemicals on the plant material. Pseudophytodermatitis from mites in the wheat and/or barley plant can occur at harvest time when contact with the plant material is high. Insects such as the North American itch mite (Pediculoides ventricosus) can cause petechiae, wheals, and pustules. In addition, insecticides such as malathion and arsenical sprays that are applied to plant leaves can cause pseudophytodermatitis, which may be initially diagnosed as dermatitis to the plant itself.⁶

Patch Testing to Plants

When a patient presents with recurrent or persistent dermatitis and a plant contact allergen is suspected, patch testing is indicated. Most comprehensive patch test series contain various plant allergens, such as sesquiterpene lactones, Compositae mix, and limonene hydroperoxides, and patch testing to a specialized plant series may be necessary. Poison ivy/oak/sumac allergens typically are not included in patch test series because of the high prevalence of allergic reactions to these chemicals and the likelihood of sensitization when patch testing with urushiol. Compositae contact sensitization can be difficult to diagnose because neither sesquiterpene lactone mix 0.1% nor parthenolide 0.1% are sensitive enough to pick up all Compositae allergies.^33,34 Paulsen and Andersen³⁴ proposed that if Compositae sensitization is suspected, testing should include sesquiterpene lactone, parthenolide, and Compositae mix II 2.5%, as well as other potential Compositae allergens based on the patient’s history.³⁴

Because plants can have geographic variability and contain potentially unknown allergens,³⁵ testing to plant components may increase the diagnostic yield of patch testing. Dividing the plant into component parts (ie, stem, bulb, leaf, flower) is helpful, as different components have different allergen concentrations. It is important to consult expert resources before proceeding with plant component patch testing because irritant reactions are frequent and may confound the testing.³⁶

Prevention and Treatment

For all plant dermatoses, the mainstay of prevention is to avoid contact with the offending plant material. Gloves can be an important protective tool for plant dermatitis prevention; the correct material depends on the plant species being handled. Rubber gloves should not be worn to protect against Toxicodendron plants since the catechols in urushiol are soluble in rubber; vinyl gloves should be worn instead.⁶ Marks³⁷ found that tuliposide A, the allergen in the Peruvian lily (Alstroemeria), penetrates both vinyl and latex gloves; it does not penetrate nitrile gloves. If exposed, the risk of dermatitis can be decreased if the allergen is washed away with soap and water as soon as possible. Some allergens such as Toxicodendron are absorbed quickly and need to be washed off within 10 minutes of exposure.⁶ Importantly, exposed gardening gloves may continue to perpetuate ACD if the allergen is not also washed off the gloves themselves.

For light-mediated dermatoses, sun avoidance or use of an effective sunscreen can reduce symptoms in an individual who has already been exposed.¹⁰ UVA light activates psoralen-mediated dermatitis but not until 30 to 120 minutes after absorption into the skin.³⁸

Barrier creams are thought to be protective against plant ACD through a variety of mechanisms. The cream itself is meant to reduce skin contact to an allergen or irritant. Additionally, barrier creams contain active ingredients such as silicone, hydrocarbons, and aluminum chlorohydrate, which are thought to trap or transform offending agents before contacting the skin. When contact with a Toxicodendron species is anticipated, Marks et al³⁹ found that dermatitis was absent or significantly reduced when 144 patients were pretreated with quaternium-18 bentonite lotion 5% (P<.0001).

Although allergen avoidance and use of gloves and barrier creams are the mainstays of preventing plant dermatoses, treatment often is required to control postexposure symptoms. For all plant dermatoses, topical corticosteroids can be used to reduce inflammation and pruritus. In some cases, systemic steroids may be necessary. To prevent rebound of dermatitis, patients often require a 3-week or longer course of oral steroids to quell the reaction, particularly if the dermatitis is vigorous or an id reaction is present.⁴⁰ Antihistamines and cold compresses also can provide symptomatic relief.

Final Interpretation

Plants can cause a variety of dermatoses. Although Toxicodendron plants are the most frequent cause of ACD, it is important to keep in mind that florists, gardeners, and farmers are exposed to a large variety of allergens, irritants, and phototoxic agents that cause dermatoses as well. Confirmation of plant-induced ACD involves patch testing against suspected species. Prevention involves use of appropriate barriers and avoidance of implicated plants. Treatment includes topical steroids, antihistamines, and prednisone.

Plants can contribute to a variety of dermatoses. The Toxicodendron genus, which includes poison ivy, poison oak, and poison sumac, is a well-known and common cause of allergic contact dermatitis (ACD), but many other plants can cause direct or airborne contact dermatitis, especially in gardeners, florists, and farmers. This article provides an overview of different plant-related dermatoses and culprit plants as well as how these dermatoses should be diagnosed and treated.

Epidemiology

Plant dermatoses affect more than 50 million individuals each year.^1,2 In the United States, the Toxicodendron genus causes ACD in more than 70% of exposed individuals, leading to medical visits.³ An urgent care visit for a plant-related dermatitis is estimated to cost $168, while an emergency department visit can cost 3 times as much.⁴ Although less common, Compositae plants are another important culprit of plant dermatitis, particularly in gardeners, florists, and farmers. Data from the 2017-2018 North American Contact Dermatitis Group screening series (N=4947) showed sesquiterpene lactones and Compositae to be positive in 0.5% of patch-tested patients.⁵

Plant Dermatitis Classifications

Plant dermatitis can be classified into 5 main categories: ACD, mechanical irritant contact dermatitis, chemical irritant contact dermatitis, light-mediated dermatitis, and pseudophytodermatitis.⁶

Allergic contact dermatitis is an immune-mediated type IV delayed hypersensitivity reaction. The common molecular allergens in plants include phenols, α-methylene-γ-butyrolactones, quinones, terpenes, disulfides, isothiocyanates, and polyacetylenic derivatives.⁶

Plant contact dermatitis due to mechanical and chemical irritants is precipitated by multiple mechanisms, including disruption of the epidermal barrier and subsequent cytokine release from keratinocytes.⁷ Nonimmunologic contact urticaria from plants is thought to be a type of irritant reaction precipitated by mechanical or chemical trauma.⁸

Light-mediated dermatitis includes phytophotodermatitis and photoallergic contact dermatitis. Phytophotodermatitis is a phototoxic reaction triggered by exposure to both plant-derived furanocoumarin and UVA light.⁹ By contrast, photoallergic contact dermatitis is a delayed hypersensitivity reaction from prior sensitization to a light-activated antigen.¹⁰

Pseudophytodermatitis, as its name implies, is not truly mediated by an allergen or irritant intrinsic to the plant but rather by dyes, waxes, insecticides, or arthropods that inhabit the plant or are secondarily applied.⁶

Common Plant Allergens

Anacardiaceae Family
Most of the allergenic plants within the Anacardiaceae family belong to the Toxicodendron genus, which encompasses poison ivy (Toxicodendron radicans), poison oak (Toxicodendron pubescens,Toxicodendron quercifolium, Toxicodendron diversiloum), and poison sumac (Toxicodendron vernix). Poison ivy is the celebrity of the Anacardiaceae family and contributes to most cases of plant-related ACD. It is found in every state in the continental United States. Poison oak is another common culprit found in the western and southeastern United States.¹¹ Plants within the Anacardiaceae family contain an oleoresin called urushiol, which is the primary sensitizing substance. Although poison ivy and poison oak grow well in full sun to partial shade, poison sumac typically is found in damp swampy areas east of the Rocky Mountains. Most cases of ACD related to Anacardiaceae species are due to direct contact with urushiol from a Toxicodendron plant, but burning of brush containing Toxicodendron can cause airborne exposure when urushiol oil is carried by smoke particles.¹² Sensitization to Toxicodendron can cause ACD to other Anacardiaceae species such as the Japanese lacquer tree (Toxicodendron vernicifluum), mango tree (Mangifera indica), cashew tree (Anacardium occidentale), and Indian marking nut tree (Semecarpus anacardium).⁶ Cross-reactions to components of the ginkgo tree (Ginkgo biloba) also are possible.

Toxicodendron plants can be more easily identified and avoided with knowledge of their characteristic leaf patterns. The most dependable way to identify poison ivy and poison oak species is to look for plants with 3 leaves, giving rise to the common saying, “Leaves of three, leave them be.” Poison sumac plants have groups of 7 to 13 leaves arranged as pairs along a central rib. Another helpful finding is a black deposit that Toxicodendron species leave behind following trauma to the leaves. Urushiol oxidizes when exposed to air and turns into a black deposit that can be seen on damaged leaves themselves or can be demonstrated in a black spot test to verify if a plant is a Toxicodendron species. The test is performed by gathering (carefully, without direct contact) a few leaves in a paper towel and crushing them to release sap. Within minutes, the sap will turn black if the plant is indeed a Toxicodendron species.¹³Pruritic, edematous, erythematous papules, plaques, and eventual vesicles in a linear distribution are suspicious for Toxicodendron exposure. Although your pet will not develop Toxicodendron ACD, oleoresin-contaminated pets can transfer the oils to their owners after coming into contact with these plants. Toxicodendron dermatitis also can be acquired from oleoresin-contaminated fomites such as clothing and shoes worn in the garden or when hiking. Toxicodendron dermatitis can appear at different sites on the body at different times depending on the amount of oleoresin exposure as well as epidermal thickness. For example, the oleoresin can be transferred from the hands to body areas with a thinner stratum corneum (eg, genitalia) and cause subsequent dermatitis.¹

Compositae Family
The Compositae family (also known as Asteraceae) is a large plant family with more than 20,000 species, including numerous weeds, wildflowers, and vegetables. The flowers, leaves, stems, and pollens of the Compositae family are coated by cyclic esters called sesquiterpene lactones. Mitchell and Dupuis¹⁴ showed that sesquiterpene lactones are the allergens responsible for ACD to various Compositae plants, including ragweed (Ambrosia), sneezeweed (Helenium), and chrysanthemums (Chrysanthemum). Common Compositae vegetables such as lettuce (Lactuca sativa) have been reported to cause ACD in chefs, grocery store produce handlers, gardeners, and even owners of lettuce-eating pet guinea pigs and turtles.¹⁵ Similarly, artichokes (Cynara scolymus) can cause ACD in gardeners.¹⁶ Exposure to Compositae species also has been implicated in photoallergic reactions, and studies have demonstrated that some patients with chronic actinic dermatitis also have positive patch test reactions to Compositae species and/or sesquiterpene lactones.^17,18

In addition to direct contact with Compositae plants, airborne exposure to sesquiterpene lactones can cause ACD.¹⁴ The pattern of airborne contact dermatitis typically involves exposed areas such as the eyelids, central face, and/or neck. The beak sign also can be a clue to airborne contact dermatitis, which involves dermatitis of the face that spares the nasal tip and/or nasal ridge. It is thought that the beak sign may result from increased sebaceous gland concentration on the nose, which prevents penetration of allergens and irritants.¹⁹ Unlike photoallergic contact dermatitis, which also can involve the face, airborne ACD frequently involves photoprotected areas such as the submandibular chin and the upper lip. Davies and Kersey²⁰ reported the case of a groundsman who was cutting grass with dandelions (Taraxacum officinale) and was found to have associated airborne ACD of the face, neck, and forearms due to Compositae allergy. In a different setting, the aromas of chamomile (Matricaria chamomilla) have been reported to cause airborne ACD in a tea drinker.²¹ Paulsen²² found that ingestion of chamomile tea can induce systemic ACD in sensitized individuals.

Alstroemeriaceae, Liliaceae, and Primulaceae
Florists are exposed to many plant species and have a high prevalence of ACD. Thiboutot et al²³ found that 15 of 57 (26%) floral workers experienced hand dermatitis that cleared with time away from work. The Peruvian lily (Alstroemeria, Alstroemeriaceae family), which contains tuliposide A, was found to be the leading cause of sensitization.²³ Tulips (Tulipa, Liliaceae family), as the flower name suggests, also contain tuliposide A, which along with mechanical irritation from the course tecta fibers on the bulbs lead to a dermatitis known as tulip fingers.^24,25 Poison primrose (Primula obconica, Primulaceae family), cultivated for its highly colorful flowers, contains the contact allergen primin.⁶ A common clinical presentation of ACD for any of these culprit flowers is localized dermatitis of the thumb and index finger in a florist or gardener.

Plants That Cause Irritant Reactions

Cactuses
Although the long spines of the Cactaceae family of cactuses is a warning for passersby, it is the small and nearly invisible barbed hairs (glochids) that inflict a more dramatic cutaneous reaction. The prickly pear cactus (Opuntia species) is a good example of such a plant, as its glochids cause mechanical irritation but also can become embedded in the skin and result in subcutaneous granulomas known as sabra dermatitis.²⁶

Stinging Nettle
The dermatologic term urticaria owes its namesake to the stinging nettle plant, which comes from the family Urticaceae. The stinging nettle has small hairs on its leaves, referred to as stinging trichomes, which have needlelike tips that pierce the skin and inject a mix of histamine, formic acid, and acetylcholine, causing a pruritic dermatitis that may last up to 12 hours.²⁷ The plant is found worldwide and is a common weed in North America.

Phytophotodermatitis

Lemons and limes (Rutaceae family) are common culprits of phytophotodermatitis, often causing what is known as a margarita burn after outdoor consumption or preparation of this tasty citrus beverage.²⁸ An accidental spray of lime juice on the skin while adding it to a beer, guacamole, salsa, or any other food or beverage also can cause phytophotodermatitis.^29-31 Although the juice of lemons and limes contains psoralens, the rind can contain a 6- to 186-fold increased concentration.³² Psoralen is the photoactive agent in Rutaceae plants that intercalates in double-stranded DNA and promotes intrastrand cross-links when exposed to UVA light, which ultimately leads to dermatitis.⁹ Phytophotodermatitis commonly causes erythema, edema, and painful bullae on sun-exposed areas and classically heals with hyperpigmentation.

Pseudophytodermatitis can occur in grain farmers and harvesters who handle wheat and/or barley and incidentally come in contact with insects and chemicals on the plant material. Pseudophytodermatitis from mites in the wheat and/or barley plant can occur at harvest time when contact with the plant material is high. Insects such as the North American itch mite (Pediculoides ventricosus) can cause petechiae, wheals, and pustules. In addition, insecticides such as malathion and arsenical sprays that are applied to plant leaves can cause pseudophytodermatitis, which may be initially diagnosed as dermatitis to the plant itself.⁶

Patch Testing to Plants

When a patient presents with recurrent or persistent dermatitis and a plant contact allergen is suspected, patch testing is indicated. Most comprehensive patch test series contain various plant allergens, such as sesquiterpene lactones, Compositae mix, and limonene hydroperoxides, and patch testing to a specialized plant series may be necessary. Poison ivy/oak/sumac allergens typically are not included in patch test series because of the high prevalence of allergic reactions to these chemicals and the likelihood of sensitization when patch testing with urushiol. Compositae contact sensitization can be difficult to diagnose because neither sesquiterpene lactone mix 0.1% nor parthenolide 0.1% are sensitive enough to pick up all Compositae allergies.^33,34 Paulsen and Andersen³⁴ proposed that if Compositae sensitization is suspected, testing should include sesquiterpene lactone, parthenolide, and Compositae mix II 2.5%, as well as other potential Compositae allergens based on the patient’s history.³⁴

Because plants can have geographic variability and contain potentially unknown allergens,³⁵ testing to plant components may increase the diagnostic yield of patch testing. Dividing the plant into component parts (ie, stem, bulb, leaf, flower) is helpful, as different components have different allergen concentrations. It is important to consult expert resources before proceeding with plant component patch testing because irritant reactions are frequent and may confound the testing.³⁶

Prevention and Treatment

For all plant dermatoses, the mainstay of prevention is to avoid contact with the offending plant material. Gloves can be an important protective tool for plant dermatitis prevention; the correct material depends on the plant species being handled. Rubber gloves should not be worn to protect against Toxicodendron plants since the catechols in urushiol are soluble in rubber; vinyl gloves should be worn instead.⁶ Marks³⁷ found that tuliposide A, the allergen in the Peruvian lily (Alstroemeria), penetrates both vinyl and latex gloves; it does not penetrate nitrile gloves. If exposed, the risk of dermatitis can be decreased if the allergen is washed away with soap and water as soon as possible. Some allergens such as Toxicodendron are absorbed quickly and need to be washed off within 10 minutes of exposure.⁶ Importantly, exposed gardening gloves may continue to perpetuate ACD if the allergen is not also washed off the gloves themselves.

For light-mediated dermatoses, sun avoidance or use of an effective sunscreen can reduce symptoms in an individual who has already been exposed.¹⁰ UVA light activates psoralen-mediated dermatitis but not until 30 to 120 minutes after absorption into the skin.³⁸

Barrier creams are thought to be protective against plant ACD through a variety of mechanisms. The cream itself is meant to reduce skin contact to an allergen or irritant. Additionally, barrier creams contain active ingredients such as silicone, hydrocarbons, and aluminum chlorohydrate, which are thought to trap or transform offending agents before contacting the skin. When contact with a Toxicodendron species is anticipated, Marks et al³⁹ found that dermatitis was absent or significantly reduced when 144 patients were pretreated with quaternium-18 bentonite lotion 5% (P<.0001).

Although allergen avoidance and use of gloves and barrier creams are the mainstays of preventing plant dermatoses, treatment often is required to control postexposure symptoms. For all plant dermatoses, topical corticosteroids can be used to reduce inflammation and pruritus. In some cases, systemic steroids may be necessary. To prevent rebound of dermatitis, patients often require a 3-week or longer course of oral steroids to quell the reaction, particularly if the dermatitis is vigorous or an id reaction is present.⁴⁰ Antihistamines and cold compresses also can provide symptomatic relief.

Final Interpretation

Plants can cause a variety of dermatoses. Although Toxicodendron plants are the most frequent cause of ACD, it is important to keep in mind that florists, gardeners, and farmers are exposed to a large variety of allergens, irritants, and phototoxic agents that cause dermatoses as well. Confirmation of plant-induced ACD involves patch testing against suspected species. Prevention involves use of appropriate barriers and avoidance of implicated plants. Treatment includes topical steroids, antihistamines, and prednisone.

Plants can contribute to a variety of dermatoses. The Toxicodendron genus, which includes poison ivy, poison oak, and poison sumac, is a well-known and common cause of allergic contact dermatitis (ACD), but many other plants can cause direct or airborne contact dermatitis, especially in gardeners, florists, and farmers. This article provides an overview of different plant-related dermatoses and culprit plants as well as how these dermatoses should be diagnosed and treated.

Epidemiology

Plant dermatoses affect more than 50 million individuals each year.^1,2 In the United States, the Toxicodendron genus causes ACD in more than 70% of exposed individuals, leading to medical visits.³ An urgent care visit for a plant-related dermatitis is estimated to cost $168, while an emergency department visit can cost 3 times as much.⁴ Although less common, Compositae plants are another important culprit of plant dermatitis, particularly in gardeners, florists, and farmers. Data from the 2017-2018 North American Contact Dermatitis Group screening series (N=4947) showed sesquiterpene lactones and Compositae to be positive in 0.5% of patch-tested patients.⁵

Plant Dermatitis Classifications

Plant dermatitis can be classified into 5 main categories: ACD, mechanical irritant contact dermatitis, chemical irritant contact dermatitis, light-mediated dermatitis, and pseudophytodermatitis.⁶

Allergic contact dermatitis is an immune-mediated type IV delayed hypersensitivity reaction. The common molecular allergens in plants include phenols, α-methylene-γ-butyrolactones, quinones, terpenes, disulfides, isothiocyanates, and polyacetylenic derivatives.⁶

Plant contact dermatitis due to mechanical and chemical irritants is precipitated by multiple mechanisms, including disruption of the epidermal barrier and subsequent cytokine release from keratinocytes.⁷ Nonimmunologic contact urticaria from plants is thought to be a type of irritant reaction precipitated by mechanical or chemical trauma.⁸

Light-mediated dermatitis includes phytophotodermatitis and photoallergic contact dermatitis. Phytophotodermatitis is a phototoxic reaction triggered by exposure to both plant-derived furanocoumarin and UVA light.⁹ By contrast, photoallergic contact dermatitis is a delayed hypersensitivity reaction from prior sensitization to a light-activated antigen.¹⁰

Pseudophytodermatitis, as its name implies, is not truly mediated by an allergen or irritant intrinsic to the plant but rather by dyes, waxes, insecticides, or arthropods that inhabit the plant or are secondarily applied.⁶

Common Plant Allergens

Anacardiaceae Family
Most of the allergenic plants within the Anacardiaceae family belong to the Toxicodendron genus, which encompasses poison ivy (Toxicodendron radicans), poison oak (Toxicodendron pubescens,Toxicodendron quercifolium, Toxicodendron diversiloum), and poison sumac (Toxicodendron vernix). Poison ivy is the celebrity of the Anacardiaceae family and contributes to most cases of plant-related ACD. It is found in every state in the continental United States. Poison oak is another common culprit found in the western and southeastern United States.¹¹ Plants within the Anacardiaceae family contain an oleoresin called urushiol, which is the primary sensitizing substance. Although poison ivy and poison oak grow well in full sun to partial shade, poison sumac typically is found in damp swampy areas east of the Rocky Mountains. Most cases of ACD related to Anacardiaceae species are due to direct contact with urushiol from a Toxicodendron plant, but burning of brush containing Toxicodendron can cause airborne exposure when urushiol oil is carried by smoke particles.¹² Sensitization to Toxicodendron can cause ACD to other Anacardiaceae species such as the Japanese lacquer tree (Toxicodendron vernicifluum), mango tree (Mangifera indica), cashew tree (Anacardium occidentale), and Indian marking nut tree (Semecarpus anacardium).⁶ Cross-reactions to components of the ginkgo tree (Ginkgo biloba) also are possible.

Toxicodendron plants can be more easily identified and avoided with knowledge of their characteristic leaf patterns. The most dependable way to identify poison ivy and poison oak species is to look for plants with 3 leaves, giving rise to the common saying, “Leaves of three, leave them be.” Poison sumac plants have groups of 7 to 13 leaves arranged as pairs along a central rib. Another helpful finding is a black deposit that Toxicodendron species leave behind following trauma to the leaves. Urushiol oxidizes when exposed to air and turns into a black deposit that can be seen on damaged leaves themselves or can be demonstrated in a black spot test to verify if a plant is a Toxicodendron species. The test is performed by gathering (carefully, without direct contact) a few leaves in a paper towel and crushing them to release sap. Within minutes, the sap will turn black if the plant is indeed a Toxicodendron species.¹³Pruritic, edematous, erythematous papules, plaques, and eventual vesicles in a linear distribution are suspicious for Toxicodendron exposure. Although your pet will not develop Toxicodendron ACD, oleoresin-contaminated pets can transfer the oils to their owners after coming into contact with these plants. Toxicodendron dermatitis also can be acquired from oleoresin-contaminated fomites such as clothing and shoes worn in the garden or when hiking. Toxicodendron dermatitis can appear at different sites on the body at different times depending on the amount of oleoresin exposure as well as epidermal thickness. For example, the oleoresin can be transferred from the hands to body areas with a thinner stratum corneum (eg, genitalia) and cause subsequent dermatitis.¹

Compositae Family
The Compositae family (also known as Asteraceae) is a large plant family with more than 20,000 species, including numerous weeds, wildflowers, and vegetables. The flowers, leaves, stems, and pollens of the Compositae family are coated by cyclic esters called sesquiterpene lactones. Mitchell and Dupuis¹⁴ showed that sesquiterpene lactones are the allergens responsible for ACD to various Compositae plants, including ragweed (Ambrosia), sneezeweed (Helenium), and chrysanthemums (Chrysanthemum). Common Compositae vegetables such as lettuce (Lactuca sativa) have been reported to cause ACD in chefs, grocery store produce handlers, gardeners, and even owners of lettuce-eating pet guinea pigs and turtles.¹⁵ Similarly, artichokes (Cynara scolymus) can cause ACD in gardeners.¹⁶ Exposure to Compositae species also has been implicated in photoallergic reactions, and studies have demonstrated that some patients with chronic actinic dermatitis also have positive patch test reactions to Compositae species and/or sesquiterpene lactones.^17,18

In addition to direct contact with Compositae plants, airborne exposure to sesquiterpene lactones can cause ACD.¹⁴ The pattern of airborne contact dermatitis typically involves exposed areas such as the eyelids, central face, and/or neck. The beak sign also can be a clue to airborne contact dermatitis, which involves dermatitis of the face that spares the nasal tip and/or nasal ridge. It is thought that the beak sign may result from increased sebaceous gland concentration on the nose, which prevents penetration of allergens and irritants.¹⁹ Unlike photoallergic contact dermatitis, which also can involve the face, airborne ACD frequently involves photoprotected areas such as the submandibular chin and the upper lip. Davies and Kersey²⁰ reported the case of a groundsman who was cutting grass with dandelions (Taraxacum officinale) and was found to have associated airborne ACD of the face, neck, and forearms due to Compositae allergy. In a different setting, the aromas of chamomile (Matricaria chamomilla) have been reported to cause airborne ACD in a tea drinker.²¹ Paulsen²² found that ingestion of chamomile tea can induce systemic ACD in sensitized individuals.

Alstroemeriaceae, Liliaceae, and Primulaceae
Florists are exposed to many plant species and have a high prevalence of ACD. Thiboutot et al²³ found that 15 of 57 (26%) floral workers experienced hand dermatitis that cleared with time away from work. The Peruvian lily (Alstroemeria, Alstroemeriaceae family), which contains tuliposide A, was found to be the leading cause of sensitization.²³ Tulips (Tulipa, Liliaceae family), as the flower name suggests, also contain tuliposide A, which along with mechanical irritation from the course tecta fibers on the bulbs lead to a dermatitis known as tulip fingers.^24,25 Poison primrose (Primula obconica, Primulaceae family), cultivated for its highly colorful flowers, contains the contact allergen primin.⁶ A common clinical presentation of ACD for any of these culprit flowers is localized dermatitis of the thumb and index finger in a florist or gardener.

Plants That Cause Irritant Reactions

Cactuses
Although the long spines of the Cactaceae family of cactuses is a warning for passersby, it is the small and nearly invisible barbed hairs (glochids) that inflict a more dramatic cutaneous reaction. The prickly pear cactus (Opuntia species) is a good example of such a plant, as its glochids cause mechanical irritation but also can become embedded in the skin and result in subcutaneous granulomas known as sabra dermatitis.²⁶

Stinging Nettle
The dermatologic term urticaria owes its namesake to the stinging nettle plant, which comes from the family Urticaceae. The stinging nettle has small hairs on its leaves, referred to as stinging trichomes, which have needlelike tips that pierce the skin and inject a mix of histamine, formic acid, and acetylcholine, causing a pruritic dermatitis that may last up to 12 hours.²⁷ The plant is found worldwide and is a common weed in North America.

Phytophotodermatitis

Lemons and limes (Rutaceae family) are common culprits of phytophotodermatitis, often causing what is known as a margarita burn after outdoor consumption or preparation of this tasty citrus beverage.²⁸ An accidental spray of lime juice on the skin while adding it to a beer, guacamole, salsa, or any other food or beverage also can cause phytophotodermatitis.^29-31 Although the juice of lemons and limes contains psoralens, the rind can contain a 6- to 186-fold increased concentration.³² Psoralen is the photoactive agent in Rutaceae plants that intercalates in double-stranded DNA and promotes intrastrand cross-links when exposed to UVA light, which ultimately leads to dermatitis.⁹ Phytophotodermatitis commonly causes erythema, edema, and painful bullae on sun-exposed areas and classically heals with hyperpigmentation.

Pseudophytodermatitis can occur in grain farmers and harvesters who handle wheat and/or barley and incidentally come in contact with insects and chemicals on the plant material. Pseudophytodermatitis from mites in the wheat and/or barley plant can occur at harvest time when contact with the plant material is high. Insects such as the North American itch mite (Pediculoides ventricosus) can cause petechiae, wheals, and pustules. In addition, insecticides such as malathion and arsenical sprays that are applied to plant leaves can cause pseudophytodermatitis, which may be initially diagnosed as dermatitis to the plant itself.⁶

Patch Testing to Plants

When a patient presents with recurrent or persistent dermatitis and a plant contact allergen is suspected, patch testing is indicated. Most comprehensive patch test series contain various plant allergens, such as sesquiterpene lactones, Compositae mix, and limonene hydroperoxides, and patch testing to a specialized plant series may be necessary. Poison ivy/oak/sumac allergens typically are not included in patch test series because of the high prevalence of allergic reactions to these chemicals and the likelihood of sensitization when patch testing with urushiol. Compositae contact sensitization can be difficult to diagnose because neither sesquiterpene lactone mix 0.1% nor parthenolide 0.1% are sensitive enough to pick up all Compositae allergies.^33,34 Paulsen and Andersen³⁴ proposed that if Compositae sensitization is suspected, testing should include sesquiterpene lactone, parthenolide, and Compositae mix II 2.5%, as well as other potential Compositae allergens based on the patient’s history.³⁴

Because plants can have geographic variability and contain potentially unknown allergens,³⁵ testing to plant components may increase the diagnostic yield of patch testing. Dividing the plant into component parts (ie, stem, bulb, leaf, flower) is helpful, as different components have different allergen concentrations. It is important to consult expert resources before proceeding with plant component patch testing because irritant reactions are frequent and may confound the testing.³⁶

Prevention and Treatment

For all plant dermatoses, the mainstay of prevention is to avoid contact with the offending plant material. Gloves can be an important protective tool for plant dermatitis prevention; the correct material depends on the plant species being handled. Rubber gloves should not be worn to protect against Toxicodendron plants since the catechols in urushiol are soluble in rubber; vinyl gloves should be worn instead.⁶ Marks³⁷ found that tuliposide A, the allergen in the Peruvian lily (Alstroemeria), penetrates both vinyl and latex gloves; it does not penetrate nitrile gloves. If exposed, the risk of dermatitis can be decreased if the allergen is washed away with soap and water as soon as possible. Some allergens such as Toxicodendron are absorbed quickly and need to be washed off within 10 minutes of exposure.⁶ Importantly, exposed gardening gloves may continue to perpetuate ACD if the allergen is not also washed off the gloves themselves.

For light-mediated dermatoses, sun avoidance or use of an effective sunscreen can reduce symptoms in an individual who has already been exposed.¹⁰ UVA light activates psoralen-mediated dermatitis but not until 30 to 120 minutes after absorption into the skin.³⁸

Barrier creams are thought to be protective against plant ACD through a variety of mechanisms. The cream itself is meant to reduce skin contact to an allergen or irritant. Additionally, barrier creams contain active ingredients such as silicone, hydrocarbons, and aluminum chlorohydrate, which are thought to trap or transform offending agents before contacting the skin. When contact with a Toxicodendron species is anticipated, Marks et al³⁹ found that dermatitis was absent or significantly reduced when 144 patients were pretreated with quaternium-18 bentonite lotion 5% (P<.0001).

Although allergen avoidance and use of gloves and barrier creams are the mainstays of preventing plant dermatoses, treatment often is required to control postexposure symptoms. For all plant dermatoses, topical corticosteroids can be used to reduce inflammation and pruritus. In some cases, systemic steroids may be necessary. To prevent rebound of dermatitis, patients often require a 3-week or longer course of oral steroids to quell the reaction, particularly if the dermatitis is vigorous or an id reaction is present.⁴⁰ Antihistamines and cold compresses also can provide symptomatic relief.

Final Interpretation

Plants can cause a variety of dermatoses. Although Toxicodendron plants are the most frequent cause of ACD, it is important to keep in mind that florists, gardeners, and farmers are exposed to a large variety of allergens, irritants, and phototoxic agents that cause dermatoses as well. Confirmation of plant-induced ACD involves patch testing against suspected species. Prevention involves use of appropriate barriers and avoidance of implicated plants. Treatment includes topical steroids, antihistamines, and prednisone.

A new study rebuts the conventional rheumatology wisdom about ankylosing spondylitis (AS) by reporting that actually there’s no gender gap in the prevalence of the disease. Researchers found no statistically significant difference in rates between men and women based on an analysis of military medical records.

feellife/Thinkstock

“Our findings challenge the widely held belief that AS in the U.S. occurs substantially more frequently in males than females,” the study authors, led by data scientist D. Alan Nelson, PhD, of Stanford (Calif.) University, wrote in a study published Aug. 30 in Arthritis Care & Research.

The researchers launched the study to fill a gap in knowledge regarding case rates by gender. “The incidence of AS in the U.S. has been understudied and incompletely characterized,” they wrote.

Even though AS is fairly common, affecting an estimated 1% of the American adult population (2.5 million people), only one published population study has examined rates by gender in the United States. That study tracked cases in Minnesota’s Olmsted County during 1980-2009 and found that the ratio of cases in men vs. women was 3.8:1, which was “consistent with more recent estimates” at the time.

However, the population in that study in 1980 was 100% White, the authors of the new study note. A Canadian study that tracked an Ontario population from 1995 to 2010, meanwhile, suggested that AS rates among women were rising and the gender gap was shrinking. AS rates as a whole also nearly tripled, possibly because of more awareness.

For the new study, researchers retrospectively tracked 728,556 members of the U.S. military who underwent guideline-directed screening for back pain during 2014-2017. The study population was about 68% White, 22% Black, 5% Asian or Pacific Islander, and the remainder were other races or unknown. About 85% were male.

The subjects were monitored for a mean of 2.21 years, and 438 (0.06%) were diagnosed with AS at least once over that period.

The researchers found that the AS rates among males vs. females were similar (incidence rate ratio, 1.16; P = .23; adjusted odds ratio, 0.79; 95% confidence interval, 0.61-1.02; P = .072).

The researchers also found that Whites were more likely to develop AS than Blacks (aOR, 1.39; 95% CI, 1.01-1.66; P = .04).

The risk of AS increased with age, the researchers reported, with the odds growing sevenfold in the 45-and-older population vs. the under-24 population (aOR, 7.3; 95% CI, 5.7-10.3; P < .001).

The researchers noted that their study examined a more diverse population than the earlier Minnesota study. It’s also possible that the results of the two studies differed because of differences in definitions of AS diagnosis or imprecision in diagnosis codes, they wrote.

The researchers added that “the finding of a 1.21 male-female prevalence ratio of AS in the Canadian Ontario study was also generally consistent with our findings. Similar to our study population, the Canadian population was racially more diverse than the Olmsted study population at the times of both studies.”

Some limitations of the study include the fact that the military population is not a random sample and may have low rates of AS. “It is highly likely that most clinically evident cases of AS would have been screened out prior to enrollment in the military service,” they wrote. “Differences between military service members and the general population may explain why we observed a different association between AS incidence and age in comparison to that reported by prior studies. The increasing risk of AS with adult age that we observed could reflect selective discharge patterns related to very early symptoms of AS in this population.”

The study was funded in part by a grant from the Spondylitis Association of America. No information about potential conflicts of interest was provided in the manuscript.

A new study rebuts the conventional rheumatology wisdom about ankylosing spondylitis (AS) by reporting that actually there’s no gender gap in the prevalence of the disease. Researchers found no statistically significant difference in rates between men and women based on an analysis of military medical records.

feellife/Thinkstock

“Our findings challenge the widely held belief that AS in the U.S. occurs substantially more frequently in males than females,” the study authors, led by data scientist D. Alan Nelson, PhD, of Stanford (Calif.) University, wrote in a study published Aug. 30 in Arthritis Care & Research.

The researchers launched the study to fill a gap in knowledge regarding case rates by gender. “The incidence of AS in the U.S. has been understudied and incompletely characterized,” they wrote.

Even though AS is fairly common, affecting an estimated 1% of the American adult population (2.5 million people), only one published population study has examined rates by gender in the United States. That study tracked cases in Minnesota’s Olmsted County during 1980-2009 and found that the ratio of cases in men vs. women was 3.8:1, which was “consistent with more recent estimates” at the time.

However, the population in that study in 1980 was 100% White, the authors of the new study note. A Canadian study that tracked an Ontario population from 1995 to 2010, meanwhile, suggested that AS rates among women were rising and the gender gap was shrinking. AS rates as a whole also nearly tripled, possibly because of more awareness.

For the new study, researchers retrospectively tracked 728,556 members of the U.S. military who underwent guideline-directed screening for back pain during 2014-2017. The study population was about 68% White, 22% Black, 5% Asian or Pacific Islander, and the remainder were other races or unknown. About 85% were male.

The subjects were monitored for a mean of 2.21 years, and 438 (0.06%) were diagnosed with AS at least once over that period.

The researchers found that the AS rates among males vs. females were similar (incidence rate ratio, 1.16; P = .23; adjusted odds ratio, 0.79; 95% confidence interval, 0.61-1.02; P = .072).

The researchers also found that Whites were more likely to develop AS than Blacks (aOR, 1.39; 95% CI, 1.01-1.66; P = .04).

The risk of AS increased with age, the researchers reported, with the odds growing sevenfold in the 45-and-older population vs. the under-24 population (aOR, 7.3; 95% CI, 5.7-10.3; P < .001).

The researchers noted that their study examined a more diverse population than the earlier Minnesota study. It’s also possible that the results of the two studies differed because of differences in definitions of AS diagnosis or imprecision in diagnosis codes, they wrote.

The researchers added that “the finding of a 1.21 male-female prevalence ratio of AS in the Canadian Ontario study was also generally consistent with our findings. Similar to our study population, the Canadian population was racially more diverse than the Olmsted study population at the times of both studies.”

Some limitations of the study include the fact that the military population is not a random sample and may have low rates of AS. “It is highly likely that most clinically evident cases of AS would have been screened out prior to enrollment in the military service,” they wrote. “Differences between military service members and the general population may explain why we observed a different association between AS incidence and age in comparison to that reported by prior studies. The increasing risk of AS with adult age that we observed could reflect selective discharge patterns related to very early symptoms of AS in this population.”

The study was funded in part by a grant from the Spondylitis Association of America. No information about potential conflicts of interest was provided in the manuscript.

A new study rebuts the conventional rheumatology wisdom about ankylosing spondylitis (AS) by reporting that actually there’s no gender gap in the prevalence of the disease. Researchers found no statistically significant difference in rates between men and women based on an analysis of military medical records.

feellife/Thinkstock

“Our findings challenge the widely held belief that AS in the U.S. occurs substantially more frequently in males than females,” the study authors, led by data scientist D. Alan Nelson, PhD, of Stanford (Calif.) University, wrote in a study published Aug. 30 in Arthritis Care & Research.

The researchers launched the study to fill a gap in knowledge regarding case rates by gender. “The incidence of AS in the U.S. has been understudied and incompletely characterized,” they wrote.

Even though AS is fairly common, affecting an estimated 1% of the American adult population (2.5 million people), only one published population study has examined rates by gender in the United States. That study tracked cases in Minnesota’s Olmsted County during 1980-2009 and found that the ratio of cases in men vs. women was 3.8:1, which was “consistent with more recent estimates” at the time.

However, the population in that study in 1980 was 100% White, the authors of the new study note. A Canadian study that tracked an Ontario population from 1995 to 2010, meanwhile, suggested that AS rates among women were rising and the gender gap was shrinking. AS rates as a whole also nearly tripled, possibly because of more awareness.

For the new study, researchers retrospectively tracked 728,556 members of the U.S. military who underwent guideline-directed screening for back pain during 2014-2017. The study population was about 68% White, 22% Black, 5% Asian or Pacific Islander, and the remainder were other races or unknown. About 85% were male.

The subjects were monitored for a mean of 2.21 years, and 438 (0.06%) were diagnosed with AS at least once over that period.

The researchers found that the AS rates among males vs. females were similar (incidence rate ratio, 1.16; P = .23; adjusted odds ratio, 0.79; 95% confidence interval, 0.61-1.02; P = .072).

The researchers also found that Whites were more likely to develop AS than Blacks (aOR, 1.39; 95% CI, 1.01-1.66; P = .04).

The risk of AS increased with age, the researchers reported, with the odds growing sevenfold in the 45-and-older population vs. the under-24 population (aOR, 7.3; 95% CI, 5.7-10.3; P < .001).

The researchers noted that their study examined a more diverse population than the earlier Minnesota study. It’s also possible that the results of the two studies differed because of differences in definitions of AS diagnosis or imprecision in diagnosis codes, they wrote.

The researchers added that “the finding of a 1.21 male-female prevalence ratio of AS in the Canadian Ontario study was also generally consistent with our findings. Similar to our study population, the Canadian population was racially more diverse than the Olmsted study population at the times of both studies.”

Some limitations of the study include the fact that the military population is not a random sample and may have low rates of AS. “It is highly likely that most clinically evident cases of AS would have been screened out prior to enrollment in the military service,” they wrote. “Differences between military service members and the general population may explain why we observed a different association between AS incidence and age in comparison to that reported by prior studies. The increasing risk of AS with adult age that we observed could reflect selective discharge patterns related to very early symptoms of AS in this population.”

The study was funded in part by a grant from the Spondylitis Association of America. No information about potential conflicts of interest was provided in the manuscript.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

The COVID-19 pandemic is a worldwide tragedy. In the beginning there was a lack of testing, personal protective equipment, COVID tests, and support for health care workers and patients. As 2020 came to a close, the world was given a glimpse of hope with the development of a vaccine against the deadly virus. Many world citizens celebrated the scientific accomplishment and began to breathe a sigh of relief that there was an end in sight. However, the development and distribution of the COVID-19 vaccine revealed a new challenge, vaccine hesitancy.

Community members, young healthy people, and even critically ill hospitalized patients who have the fortune of surviving acute illness are hesitant to the COVID-19 vaccine. I recently cared for a critically ill young patient who was intubated for days with status asthmaticus, one of the worst cases I’d ever seen. She was extubated and made a full recovery. Prior to discharge I asked if she wanted the first dose of the COVID-19 vaccine and she said, “No.” I was shocked. This was an otherwise healthy 30-something-year-old who was lucky enough to survive without any underlying infection in the setting of severe obstructive lung disease. A co-infection with COVID-19 would be disastrous and increase her mortality. I had a long talk at the bedside and asked the reason for her hesitancy. Her answer left me speechless, “I don’t know, I just don’t want to.” I ultimately convinced her that contracting COVID-19 would be a fate worse than she could imagine, and she agreed to the vaccine prior to discharge. This interaction made me ponder – “why are our patients, friends, and family members hesitant about receiving a lifesaving vaccine, especially when they are aware of how sick they or others can become without it?”

According to the World Health Organization, vaccine hesitancy refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services. Vaccine hesitancy is complex and context specific, varying across time, place, and vaccines. It is influenced by factors such as complacency, convenience, and confidence.¹ No vaccine is 100% effective. However, throughout history, the work of scientists and doctors to create vaccines saved millions of lives and revolutionized global health. Arguably, the single most life-saving innovation in the history of medicine, vaccines have eradicated smallpox, protected against whooping cough (1914), diphtheria (1926), tetanus (1938), influenza (1945) and mumps (1948), polio (1955), measles (1963), and rubella (1969), and worldwide vaccination rates increased dramatically thanks to successful global health campaigns.² However, there was a paradox of vaccine success. As terrifying diseases decreased in prevalence, so did the fear of these diseases and their effects – paralysis, brain damage, blindness, and death. This gave birth to a new challenge in modern medicine, vaccine hesitancy – a privilege of first world nations.

Vaccines saved countless lives and improved health and wellbeing around the world for decades. However, to prevent the morbidity and mortality associated with vaccine-preventable diseases and their complications, and optimize control of vaccine-preventable diseases in communities, high vaccination rates must be achieved. Enter the COVID-19 pandemic, the creation of the COVID-19 vaccine, and vaccine hesitancy.

The question we ask ourselves as health care providers is ‘how do we convince the skeptics and those opposed to vaccination to take the vaccine?’ The answer is complicated. If you are like me, you’ve had many conversations with people – friends, patients, family members, who are resistant to the vaccine. Very often the facts are not well received, and those discussions end in argument, high emotions, and broken relationships. With the delta variant of COVID-19 on the rise, spreading aggressively among the unvaccinated, and increased hospitalizations, we foresee the reoccurrence of overwhelmed health systems and a continued death toll.

The new paradox we are faced with is that people choose to believe fiction versus fact, despite the real life evidence of the severe health effects and increased deaths related to COVID-19. Do these skeptics simply have a cavalier attitude towards not only their own life, but the lives of others? Or, is there something deeper? It is not enough to tell people that the vaccines are proven safe³ and are more widely available than ever. It is not enough to tell people that they can die of COVID-19 – they already know that. Emotional pleas to family members are falling on deaf ears. This past month, when asking patients why they don’t want the vaccine, many have no real legitimate health-related reason and respond with a simple, “I don’t want to.” So, how do we get through to the unvaccinated?
 

A compassionate approach

We navigate these difficult conversations over time with the approach of compassion and empathy, not hostility or bullying. As health care providers, we start by being good empathic listeners. Similar to when we have advance care planning and code status conversations, we cannot enter the dialogue with our intention, beliefs, or formulated goals for that person. We have to listen without judgement to the wide range of reasons why others are reluctant or unwilling to get the vaccine – historical mistrust, political identity, religious reasons, short-term side effects that may cause them to lose a day or two of work – and understand that for each person their reasons are different. The point is to not assume that you know or understand what barriers and beliefs they have towards vaccination, but to meet them at their point of view and listen while keeping your own emotions level and steady.

Identifying the reason for vaccine hesitancy is the first step to getting the unvaccinated closer to vaccination. Ask open ended questions: “Can you help me understand, what is your hesitancy to the vaccine?”; “What about the vaccine worries you?”; “What have you heard about/know about the COVID-19 vaccine?”; or “Can you tell me more about why you feel that way?” As meticulous as it sounds, we have to go back to the basics of patient interviewing.

It is important to remember that this is not a debate and escalation to arguments will certainly backfire. Think about any time you disagreed with someone on a topic. Did criticizing, blaming, and shaming ever convince you to change your beliefs or behaviors? The likely answer is, “No.” Avoid the “backfire effect”– which is when giving people facts disproving their “incorrect” beliefs can actually reinforce those beliefs. The more people are confronted with facts at odds with their opinions, the stronger they cling to those opinions. If you want them to change their mind, you cannot approach the conversation as a debate. You are having this vaccine discussion to try to meet the other person where they are, understand their position, and talk with them, and not at them, about their concerns.

As leaders in health care, we have to be willing to give up control and lead with empathy. We have to show others that we hear them, believe their concerns, and acknowledge that their beliefs are valid to them as individuals. Even if you disagree, this is not the place to let anger, disappointment, or resentment take a front seat. This is about balance, and highlighting the autonomy in decision making that the other person has to make a choice. Be humble in these conversations and avoid condescending tones or statements.

We already know that you are a caring health care provider. As hospitalists, we are frontline providers who have seen unnecessary deaths and illness due to COVID-19. You are passionate and motivated because you are committed to your oath to save lives. However, you have to check your own feelings and remember that you are not speaking with an unvaccinated person to make them get vaccinated, but rather to understand their cognitive process and hopefully walk with them down a path that provides them with a clarity of options they truly have. Extend empathy and they will see your motivation is rooted in good-heartedness and a concern for their wellbeing.

If someone admits to reasons for avoiding vaccination that are not rooted in any fact, then guide them to the best resources. Our health care system recently released a COVID-19 fact versus myth handout called Trust the Facts. This could be the kind of vetted resource you offer. Guide them to accredited websites, such as the World Health Organization, the Center for Disease Control, or their local and state departments of health to help debunk fiction by reviewing it with them. Discuss myths such as, ‘the vaccine will cause infertility,’ ‘the vaccine will give me COVID,’ ‘the vaccine was rushed and is not safe,’ ‘the vaccine is not needed if I am young and healthy,’ ‘the vaccine has a microchip,’ etc. Knowledge is power and disinformation is deadly, but how facts are presented will make the biggest difference in how others receive them, so remember your role is not to argue with these statements, but rather to provide perspective without agreeing or disagreeing.

Respond to their concerns with statements such as, “I hear you…it sounds like you are worried/fearful/mistrusting about the side effects/safety/efficacy of the vaccine…can we talk more about that?” Ask them where these concerns come from – the news, social media, an article, word of mouth, friends, or family. Ask them about the information they have and show genuine interest that you want to see it from their perspective. This is the key to compassionate and empathic dialogue – you relinquish your intentions.

Once you know or unveil their reasons for hesitancy, ask them what they would like to see with regards to COVID-19 and ending the pandemic. Would they like to get back to a new normal, to visit family members, to travel once again, to not have to wear masks and quarantine? What do they want for themselves, their families, communities, the country, or even the world? The goal is to find something in our shared humanity, to connect on a deeper level so they start to open up and let down walls, and find something you both see eye-to-eye on. Know your audience and speak to what serves them. To effectively persuade someone to come around to your point of view starts with recognizing the root of the disagreement and trying to overcome it before trying to change the person’s mind, understanding both the logic and the emotion that’s driving their decision making.⁴
 

Building trust

Reminding patients, friends or family members that their health and well-being means a lot to you can also be a strategy to keeping the conversation open and friendly. Sharing stories as hospitalists caring for many critically ill COVID patients or patients who died alone due to COVID-19, and the trauma you experienced as a health care provider feeling paralyzed by the limitations of modern medicine against the deadly virus, will only serve to humanize you in such an interaction.

Building trust will also increase vaccine willingness. This will require a concerted effort by scientists, doctors, and health care systems to engage with community leaders and members. To address hesitancy, the people we serve have to hear those local, personal, and relatable stories about vaccinations, and how it benefits not just themselves, but others around them in their community. As part of the #VaxUp campaign in Virginia, community and physician leaders shared their stories of hesitancy and motivation surrounding the vaccine. These are real people in the community discussing why getting vaccinated is so important and what helped them make an informed decision. I discussed my own hesitancy and concerns and also tackled a few vaccine myths.

As vaccinated health care workers or community leaders, you are living proof of the benefits of getting the COVID vaccine. Focus on the positives but also be honest. If your second shot gave you fevers, chills, or myalgias, then admit it and share how you overcame these expected reactions. Refocus on the safety of the vaccine and the fact that it is freely available to all people. Maybe the person you are speaking with doesn’t know where or how to get an appointment to get vaccinated. Help them find the nearest place to get an appointment and identify barriers they may have in transportation, child, or senior care to leave home safely to get vaccinated, or physical conditions that are preventing them from receiving the vaccine. Share that being vaccinated protects you from contracting the virus and spreading it to loved ones. Focus on how a fully vaccinated community and country can open up opportunities to heal and connect as a society, spend time with family/friends in another county or state, hold a newborn grandchild, or even travel outside the U.S.

There is no guarantee that you will be able to persuade someone to get vaccinated. It’s possible the outcome of your conversation will not result in the other person changing their mind in that moment. That doesn’t mean that you failed, because you started the dialogue and planted the seed. If you are a vaccinated health care provider, your words have influence and power, and we are obliged by our positions to have responsibility for the health of our communities. Don’t be discouraged, as it is through caring, compassionate, respectful, and empathic conversations that your influence will make the most difference in these relationships as you continue to advocate for all human life.
 

Dr. Williams is vice president of the Hampton Roads chapter of the Society of Hospital Medicine. She is a hospitalist at Sentara Careplex Hospital in Hampton, Va., where she also serves as vice president of the Medical Executive Committee.

References

1. World Health Organization. Report of the SAGE working group on vaccine hesitancy. Oct 2014. https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf

2. Hsu JL. A brief history of vaccines: Smallpox to the present. S D Med. 2013;Spec no:33-7. PMID: 23444589.

3. Chiu A, Bever L. Are they experimental? Can they alter DNA? Experts tackle lingering coronavirus vaccine fears. The Washington Post. 2021 May 14. https://www.washingtonpost.com/lifestyle/2021/05/14/safe-fast-vaccine-fear-infertility-dna/

4. Huang L. Edge: Turning Adversity into Advantage. New York: Portfolio/Penguin, 2020.

The COVID-19 pandemic is a worldwide tragedy. In the beginning there was a lack of testing, personal protective equipment, COVID tests, and support for health care workers and patients. As 2020 came to a close, the world was given a glimpse of hope with the development of a vaccine against the deadly virus. Many world citizens celebrated the scientific accomplishment and began to breathe a sigh of relief that there was an end in sight. However, the development and distribution of the COVID-19 vaccine revealed a new challenge, vaccine hesitancy.

Community members, young healthy people, and even critically ill hospitalized patients who have the fortune of surviving acute illness are hesitant to the COVID-19 vaccine. I recently cared for a critically ill young patient who was intubated for days with status asthmaticus, one of the worst cases I’d ever seen. She was extubated and made a full recovery. Prior to discharge I asked if she wanted the first dose of the COVID-19 vaccine and she said, “No.” I was shocked. This was an otherwise healthy 30-something-year-old who was lucky enough to survive without any underlying infection in the setting of severe obstructive lung disease. A co-infection with COVID-19 would be disastrous and increase her mortality. I had a long talk at the bedside and asked the reason for her hesitancy. Her answer left me speechless, “I don’t know, I just don’t want to.” I ultimately convinced her that contracting COVID-19 would be a fate worse than she could imagine, and she agreed to the vaccine prior to discharge. This interaction made me ponder – “why are our patients, friends, and family members hesitant about receiving a lifesaving vaccine, especially when they are aware of how sick they or others can become without it?”

According to the World Health Organization, vaccine hesitancy refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services. Vaccine hesitancy is complex and context specific, varying across time, place, and vaccines. It is influenced by factors such as complacency, convenience, and confidence.¹ No vaccine is 100% effective. However, throughout history, the work of scientists and doctors to create vaccines saved millions of lives and revolutionized global health. Arguably, the single most life-saving innovation in the history of medicine, vaccines have eradicated smallpox, protected against whooping cough (1914), diphtheria (1926), tetanus (1938), influenza (1945) and mumps (1948), polio (1955), measles (1963), and rubella (1969), and worldwide vaccination rates increased dramatically thanks to successful global health campaigns.² However, there was a paradox of vaccine success. As terrifying diseases decreased in prevalence, so did the fear of these diseases and their effects – paralysis, brain damage, blindness, and death. This gave birth to a new challenge in modern medicine, vaccine hesitancy – a privilege of first world nations.

Vaccines saved countless lives and improved health and wellbeing around the world for decades. However, to prevent the morbidity and mortality associated with vaccine-preventable diseases and their complications, and optimize control of vaccine-preventable diseases in communities, high vaccination rates must be achieved. Enter the COVID-19 pandemic, the creation of the COVID-19 vaccine, and vaccine hesitancy.

The question we ask ourselves as health care providers is ‘how do we convince the skeptics and those opposed to vaccination to take the vaccine?’ The answer is complicated. If you are like me, you’ve had many conversations with people – friends, patients, family members, who are resistant to the vaccine. Very often the facts are not well received, and those discussions end in argument, high emotions, and broken relationships. With the delta variant of COVID-19 on the rise, spreading aggressively among the unvaccinated, and increased hospitalizations, we foresee the reoccurrence of overwhelmed health systems and a continued death toll.

The new paradox we are faced with is that people choose to believe fiction versus fact, despite the real life evidence of the severe health effects and increased deaths related to COVID-19. Do these skeptics simply have a cavalier attitude towards not only their own life, but the lives of others? Or, is there something deeper? It is not enough to tell people that the vaccines are proven safe³ and are more widely available than ever. It is not enough to tell people that they can die of COVID-19 – they already know that. Emotional pleas to family members are falling on deaf ears. This past month, when asking patients why they don’t want the vaccine, many have no real legitimate health-related reason and respond with a simple, “I don’t want to.” So, how do we get through to the unvaccinated?
 

A compassionate approach

We navigate these difficult conversations over time with the approach of compassion and empathy, not hostility or bullying. As health care providers, we start by being good empathic listeners. Similar to when we have advance care planning and code status conversations, we cannot enter the dialogue with our intention, beliefs, or formulated goals for that person. We have to listen without judgement to the wide range of reasons why others are reluctant or unwilling to get the vaccine – historical mistrust, political identity, religious reasons, short-term side effects that may cause them to lose a day or two of work – and understand that for each person their reasons are different. The point is to not assume that you know or understand what barriers and beliefs they have towards vaccination, but to meet them at their point of view and listen while keeping your own emotions level and steady.

Identifying the reason for vaccine hesitancy is the first step to getting the unvaccinated closer to vaccination. Ask open ended questions: “Can you help me understand, what is your hesitancy to the vaccine?”; “What about the vaccine worries you?”; “What have you heard about/know about the COVID-19 vaccine?”; or “Can you tell me more about why you feel that way?” As meticulous as it sounds, we have to go back to the basics of patient interviewing.

It is important to remember that this is not a debate and escalation to arguments will certainly backfire. Think about any time you disagreed with someone on a topic. Did criticizing, blaming, and shaming ever convince you to change your beliefs or behaviors? The likely answer is, “No.” Avoid the “backfire effect”– which is when giving people facts disproving their “incorrect” beliefs can actually reinforce those beliefs. The more people are confronted with facts at odds with their opinions, the stronger they cling to those opinions. If you want them to change their mind, you cannot approach the conversation as a debate. You are having this vaccine discussion to try to meet the other person where they are, understand their position, and talk with them, and not at them, about their concerns.

As leaders in health care, we have to be willing to give up control and lead with empathy. We have to show others that we hear them, believe their concerns, and acknowledge that their beliefs are valid to them as individuals. Even if you disagree, this is not the place to let anger, disappointment, or resentment take a front seat. This is about balance, and highlighting the autonomy in decision making that the other person has to make a choice. Be humble in these conversations and avoid condescending tones or statements.

We already know that you are a caring health care provider. As hospitalists, we are frontline providers who have seen unnecessary deaths and illness due to COVID-19. You are passionate and motivated because you are committed to your oath to save lives. However, you have to check your own feelings and remember that you are not speaking with an unvaccinated person to make them get vaccinated, but rather to understand their cognitive process and hopefully walk with them down a path that provides them with a clarity of options they truly have. Extend empathy and they will see your motivation is rooted in good-heartedness and a concern for their wellbeing.

If someone admits to reasons for avoiding vaccination that are not rooted in any fact, then guide them to the best resources. Our health care system recently released a COVID-19 fact versus myth handout called Trust the Facts. This could be the kind of vetted resource you offer. Guide them to accredited websites, such as the World Health Organization, the Center for Disease Control, or their local and state departments of health to help debunk fiction by reviewing it with them. Discuss myths such as, ‘the vaccine will cause infertility,’ ‘the vaccine will give me COVID,’ ‘the vaccine was rushed and is not safe,’ ‘the vaccine is not needed if I am young and healthy,’ ‘the vaccine has a microchip,’ etc. Knowledge is power and disinformation is deadly, but how facts are presented will make the biggest difference in how others receive them, so remember your role is not to argue with these statements, but rather to provide perspective without agreeing or disagreeing.

Respond to their concerns with statements such as, “I hear you…it sounds like you are worried/fearful/mistrusting about the side effects/safety/efficacy of the vaccine…can we talk more about that?” Ask them where these concerns come from – the news, social media, an article, word of mouth, friends, or family. Ask them about the information they have and show genuine interest that you want to see it from their perspective. This is the key to compassionate and empathic dialogue – you relinquish your intentions.

Once you know or unveil their reasons for hesitancy, ask them what they would like to see with regards to COVID-19 and ending the pandemic. Would they like to get back to a new normal, to visit family members, to travel once again, to not have to wear masks and quarantine? What do they want for themselves, their families, communities, the country, or even the world? The goal is to find something in our shared humanity, to connect on a deeper level so they start to open up and let down walls, and find something you both see eye-to-eye on. Know your audience and speak to what serves them. To effectively persuade someone to come around to your point of view starts with recognizing the root of the disagreement and trying to overcome it before trying to change the person’s mind, understanding both the logic and the emotion that’s driving their decision making.⁴
 

Building trust

Reminding patients, friends or family members that their health and well-being means a lot to you can also be a strategy to keeping the conversation open and friendly. Sharing stories as hospitalists caring for many critically ill COVID patients or patients who died alone due to COVID-19, and the trauma you experienced as a health care provider feeling paralyzed by the limitations of modern medicine against the deadly virus, will only serve to humanize you in such an interaction.

Building trust will also increase vaccine willingness. This will require a concerted effort by scientists, doctors, and health care systems to engage with community leaders and members. To address hesitancy, the people we serve have to hear those local, personal, and relatable stories about vaccinations, and how it benefits not just themselves, but others around them in their community. As part of the #VaxUp campaign in Virginia, community and physician leaders shared their stories of hesitancy and motivation surrounding the vaccine. These are real people in the community discussing why getting vaccinated is so important and what helped them make an informed decision. I discussed my own hesitancy and concerns and also tackled a few vaccine myths.

As vaccinated health care workers or community leaders, you are living proof of the benefits of getting the COVID vaccine. Focus on the positives but also be honest. If your second shot gave you fevers, chills, or myalgias, then admit it and share how you overcame these expected reactions. Refocus on the safety of the vaccine and the fact that it is freely available to all people. Maybe the person you are speaking with doesn’t know where or how to get an appointment to get vaccinated. Help them find the nearest place to get an appointment and identify barriers they may have in transportation, child, or senior care to leave home safely to get vaccinated, or physical conditions that are preventing them from receiving the vaccine. Share that being vaccinated protects you from contracting the virus and spreading it to loved ones. Focus on how a fully vaccinated community and country can open up opportunities to heal and connect as a society, spend time with family/friends in another county or state, hold a newborn grandchild, or even travel outside the U.S.

There is no guarantee that you will be able to persuade someone to get vaccinated. It’s possible the outcome of your conversation will not result in the other person changing their mind in that moment. That doesn’t mean that you failed, because you started the dialogue and planted the seed. If you are a vaccinated health care provider, your words have influence and power, and we are obliged by our positions to have responsibility for the health of our communities. Don’t be discouraged, as it is through caring, compassionate, respectful, and empathic conversations that your influence will make the most difference in these relationships as you continue to advocate for all human life.
 

Dr. Williams is vice president of the Hampton Roads chapter of the Society of Hospital Medicine. She is a hospitalist at Sentara Careplex Hospital in Hampton, Va., where she also serves as vice president of the Medical Executive Committee.

References

1. World Health Organization. Report of the SAGE working group on vaccine hesitancy. Oct 2014. https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf

2. Hsu JL. A brief history of vaccines: Smallpox to the present. S D Med. 2013;Spec no:33-7. PMID: 23444589.

3. Chiu A, Bever L. Are they experimental? Can they alter DNA? Experts tackle lingering coronavirus vaccine fears. The Washington Post. 2021 May 14. https://www.washingtonpost.com/lifestyle/2021/05/14/safe-fast-vaccine-fear-infertility-dna/

4. Huang L. Edge: Turning Adversity into Advantage. New York: Portfolio/Penguin, 2020.

The COVID-19 pandemic is a worldwide tragedy. In the beginning there was a lack of testing, personal protective equipment, COVID tests, and support for health care workers and patients. As 2020 came to a close, the world was given a glimpse of hope with the development of a vaccine against the deadly virus. Many world citizens celebrated the scientific accomplishment and began to breathe a sigh of relief that there was an end in sight. However, the development and distribution of the COVID-19 vaccine revealed a new challenge, vaccine hesitancy.

Community members, young healthy people, and even critically ill hospitalized patients who have the fortune of surviving acute illness are hesitant to the COVID-19 vaccine. I recently cared for a critically ill young patient who was intubated for days with status asthmaticus, one of the worst cases I’d ever seen. She was extubated and made a full recovery. Prior to discharge I asked if she wanted the first dose of the COVID-19 vaccine and she said, “No.” I was shocked. This was an otherwise healthy 30-something-year-old who was lucky enough to survive without any underlying infection in the setting of severe obstructive lung disease. A co-infection with COVID-19 would be disastrous and increase her mortality. I had a long talk at the bedside and asked the reason for her hesitancy. Her answer left me speechless, “I don’t know, I just don’t want to.” I ultimately convinced her that contracting COVID-19 would be a fate worse than she could imagine, and she agreed to the vaccine prior to discharge. This interaction made me ponder – “why are our patients, friends, and family members hesitant about receiving a lifesaving vaccine, especially when they are aware of how sick they or others can become without it?”

According to the World Health Organization, vaccine hesitancy refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services. Vaccine hesitancy is complex and context specific, varying across time, place, and vaccines. It is influenced by factors such as complacency, convenience, and confidence.¹ No vaccine is 100% effective. However, throughout history, the work of scientists and doctors to create vaccines saved millions of lives and revolutionized global health. Arguably, the single most life-saving innovation in the history of medicine, vaccines have eradicated smallpox, protected against whooping cough (1914), diphtheria (1926), tetanus (1938), influenza (1945) and mumps (1948), polio (1955), measles (1963), and rubella (1969), and worldwide vaccination rates increased dramatically thanks to successful global health campaigns.² However, there was a paradox of vaccine success. As terrifying diseases decreased in prevalence, so did the fear of these diseases and their effects – paralysis, brain damage, blindness, and death. This gave birth to a new challenge in modern medicine, vaccine hesitancy – a privilege of first world nations.

Vaccines saved countless lives and improved health and wellbeing around the world for decades. However, to prevent the morbidity and mortality associated with vaccine-preventable diseases and their complications, and optimize control of vaccine-preventable diseases in communities, high vaccination rates must be achieved. Enter the COVID-19 pandemic, the creation of the COVID-19 vaccine, and vaccine hesitancy.

The question we ask ourselves as health care providers is ‘how do we convince the skeptics and those opposed to vaccination to take the vaccine?’ The answer is complicated. If you are like me, you’ve had many conversations with people – friends, patients, family members, who are resistant to the vaccine. Very often the facts are not well received, and those discussions end in argument, high emotions, and broken relationships. With the delta variant of COVID-19 on the rise, spreading aggressively among the unvaccinated, and increased hospitalizations, we foresee the reoccurrence of overwhelmed health systems and a continued death toll.

The new paradox we are faced with is that people choose to believe fiction versus fact, despite the real life evidence of the severe health effects and increased deaths related to COVID-19. Do these skeptics simply have a cavalier attitude towards not only their own life, but the lives of others? Or, is there something deeper? It is not enough to tell people that the vaccines are proven safe³ and are more widely available than ever. It is not enough to tell people that they can die of COVID-19 – they already know that. Emotional pleas to family members are falling on deaf ears. This past month, when asking patients why they don’t want the vaccine, many have no real legitimate health-related reason and respond with a simple, “I don’t want to.” So, how do we get through to the unvaccinated?
 

A compassionate approach

We navigate these difficult conversations over time with the approach of compassion and empathy, not hostility or bullying. As health care providers, we start by being good empathic listeners. Similar to when we have advance care planning and code status conversations, we cannot enter the dialogue with our intention, beliefs, or formulated goals for that person. We have to listen without judgement to the wide range of reasons why others are reluctant or unwilling to get the vaccine – historical mistrust, political identity, religious reasons, short-term side effects that may cause them to lose a day or two of work – and understand that for each person their reasons are different. The point is to not assume that you know or understand what barriers and beliefs they have towards vaccination, but to meet them at their point of view and listen while keeping your own emotions level and steady.

Identifying the reason for vaccine hesitancy is the first step to getting the unvaccinated closer to vaccination. Ask open ended questions: “Can you help me understand, what is your hesitancy to the vaccine?”; “What about the vaccine worries you?”; “What have you heard about/know about the COVID-19 vaccine?”; or “Can you tell me more about why you feel that way?” As meticulous as it sounds, we have to go back to the basics of patient interviewing.

It is important to remember that this is not a debate and escalation to arguments will certainly backfire. Think about any time you disagreed with someone on a topic. Did criticizing, blaming, and shaming ever convince you to change your beliefs or behaviors? The likely answer is, “No.” Avoid the “backfire effect”– which is when giving people facts disproving their “incorrect” beliefs can actually reinforce those beliefs. The more people are confronted with facts at odds with their opinions, the stronger they cling to those opinions. If you want them to change their mind, you cannot approach the conversation as a debate. You are having this vaccine discussion to try to meet the other person where they are, understand their position, and talk with them, and not at them, about their concerns.

As leaders in health care, we have to be willing to give up control and lead with empathy. We have to show others that we hear them, believe their concerns, and acknowledge that their beliefs are valid to them as individuals. Even if you disagree, this is not the place to let anger, disappointment, or resentment take a front seat. This is about balance, and highlighting the autonomy in decision making that the other person has to make a choice. Be humble in these conversations and avoid condescending tones or statements.

We already know that you are a caring health care provider. As hospitalists, we are frontline providers who have seen unnecessary deaths and illness due to COVID-19. You are passionate and motivated because you are committed to your oath to save lives. However, you have to check your own feelings and remember that you are not speaking with an unvaccinated person to make them get vaccinated, but rather to understand their cognitive process and hopefully walk with them down a path that provides them with a clarity of options they truly have. Extend empathy and they will see your motivation is rooted in good-heartedness and a concern for their wellbeing.

If someone admits to reasons for avoiding vaccination that are not rooted in any fact, then guide them to the best resources. Our health care system recently released a COVID-19 fact versus myth handout called Trust the Facts. This could be the kind of vetted resource you offer. Guide them to accredited websites, such as the World Health Organization, the Center for Disease Control, or their local and state departments of health to help debunk fiction by reviewing it with them. Discuss myths such as, ‘the vaccine will cause infertility,’ ‘the vaccine will give me COVID,’ ‘the vaccine was rushed and is not safe,’ ‘the vaccine is not needed if I am young and healthy,’ ‘the vaccine has a microchip,’ etc. Knowledge is power and disinformation is deadly, but how facts are presented will make the biggest difference in how others receive them, so remember your role is not to argue with these statements, but rather to provide perspective without agreeing or disagreeing.

Respond to their concerns with statements such as, “I hear you…it sounds like you are worried/fearful/mistrusting about the side effects/safety/efficacy of the vaccine…can we talk more about that?” Ask them where these concerns come from – the news, social media, an article, word of mouth, friends, or family. Ask them about the information they have and show genuine interest that you want to see it from their perspective. This is the key to compassionate and empathic dialogue – you relinquish your intentions.

Once you know or unveil their reasons for hesitancy, ask them what they would like to see with regards to COVID-19 and ending the pandemic. Would they like to get back to a new normal, to visit family members, to travel once again, to not have to wear masks and quarantine? What do they want for themselves, their families, communities, the country, or even the world? The goal is to find something in our shared humanity, to connect on a deeper level so they start to open up and let down walls, and find something you both see eye-to-eye on. Know your audience and speak to what serves them. To effectively persuade someone to come around to your point of view starts with recognizing the root of the disagreement and trying to overcome it before trying to change the person’s mind, understanding both the logic and the emotion that’s driving their decision making.⁴
 

Building trust

Reminding patients, friends or family members that their health and well-being means a lot to you can also be a strategy to keeping the conversation open and friendly. Sharing stories as hospitalists caring for many critically ill COVID patients or patients who died alone due to COVID-19, and the trauma you experienced as a health care provider feeling paralyzed by the limitations of modern medicine against the deadly virus, will only serve to humanize you in such an interaction.

Building trust will also increase vaccine willingness. This will require a concerted effort by scientists, doctors, and health care systems to engage with community leaders and members. To address hesitancy, the people we serve have to hear those local, personal, and relatable stories about vaccinations, and how it benefits not just themselves, but others around them in their community. As part of the #VaxUp campaign in Virginia, community and physician leaders shared their stories of hesitancy and motivation surrounding the vaccine. These are real people in the community discussing why getting vaccinated is so important and what helped them make an informed decision. I discussed my own hesitancy and concerns and also tackled a few vaccine myths.

As vaccinated health care workers or community leaders, you are living proof of the benefits of getting the COVID vaccine. Focus on the positives but also be honest. If your second shot gave you fevers, chills, or myalgias, then admit it and share how you overcame these expected reactions. Refocus on the safety of the vaccine and the fact that it is freely available to all people. Maybe the person you are speaking with doesn’t know where or how to get an appointment to get vaccinated. Help them find the nearest place to get an appointment and identify barriers they may have in transportation, child, or senior care to leave home safely to get vaccinated, or physical conditions that are preventing them from receiving the vaccine. Share that being vaccinated protects you from contracting the virus and spreading it to loved ones. Focus on how a fully vaccinated community and country can open up opportunities to heal and connect as a society, spend time with family/friends in another county or state, hold a newborn grandchild, or even travel outside the U.S.

There is no guarantee that you will be able to persuade someone to get vaccinated. It’s possible the outcome of your conversation will not result in the other person changing their mind in that moment. That doesn’t mean that you failed, because you started the dialogue and planted the seed. If you are a vaccinated health care provider, your words have influence and power, and we are obliged by our positions to have responsibility for the health of our communities. Don’t be discouraged, as it is through caring, compassionate, respectful, and empathic conversations that your influence will make the most difference in these relationships as you continue to advocate for all human life.
 

Dr. Williams is vice president of the Hampton Roads chapter of the Society of Hospital Medicine. She is a hospitalist at Sentara Careplex Hospital in Hampton, Va., where she also serves as vice president of the Medical Executive Committee.

References

1. World Health Organization. Report of the SAGE working group on vaccine hesitancy. Oct 2014. https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf

2. Hsu JL. A brief history of vaccines: Smallpox to the present. S D Med. 2013;Spec no:33-7. PMID: 23444589.

3. Chiu A, Bever L. Are they experimental? Can they alter DNA? Experts tackle lingering coronavirus vaccine fears. The Washington Post. 2021 May 14. https://www.washingtonpost.com/lifestyle/2021/05/14/safe-fast-vaccine-fear-infertility-dna/

4. Huang L. Edge: Turning Adversity into Advantage. New York: Portfolio/Penguin, 2020.

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.