Rosacea

In the clinical experience of Emmy Graber, MD, MBA, rosacea is in the eye of the beholder.

“It’s not really up to us as the providers as to what’s important to the patient or how bad their rosacea is,” she said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It really is up to the patient,” added Dr. Graber, president of The Dermatology Institute of Boston, who recommends asking patients about how severe they consider their rosacea to be, and what about rosacea bothers them most. Their responses may be surprising.

A study published in 2017 showed that complete resolution of even mild rosacea prolongs remission of rosacea, and most importantly, improves the quality of life for patients. “So, don’t discount what you consider to be mild rosacea in patients,” she said.

Skin care recommendations

“And don’t forget about basic skin care,” she advised. A recently published Chinese study of 999 rosacea patients and 1,010 controls with healthy skin found that a high frequency of cleansing and expansive use of cleansers were positively correlated with rosacea occurrence, suggesting that overcleansing can be a risk factor for rosacea. “Ask your patient, ‘how often are you cleaning your face?’ ” Dr. Graber suggested. “You might find that they’re overdoing it by washing three or four times a day. Several studies have shown that basic skin care alone improves rosacea.”

Skin care recommendations for patients with rosacea include avoiding chemical or physical exfoliants and alcohol-based topical products, and moisturizing and washing their faces with mild, synthetic detergent-based products rather than traditional soaps, which may further alkalinize and irritate the skin. “Patients should also be counseled to use physical-based sunscreens rather than chemical-based sunscreens,” she said.
 

Treating erythema

For treating erythema with topicals, a systematic review published in 2019 found the most evidence for brimonidine 0.33% gel, an alpha2-adrenergic agonist, and oxymetazoline 1% cream, an alpha1-adrenergic agonist. “Both of these products functionally constrict facial blood vessels,” and are Food and Drug Administration approved for treating persistent erythema, Dr. Graber said. “These products improve erythema within 3 hours of and up to 12 hours after application and overall, they are well tolerated.”

Rosacea.org

Based on clinical trial results, about 15% of patients on brimonidine report adverse reactions such as dermatitis, burning, pruritus, and erythema, compared with 8% of patients on oxymetazoline. At the same time, up to 20% of individuals on brimonidine report rebound erythema, compared with fewer than 1% of those using oxymetazoline. Laser and light therapies such as pulse-dye lasers, potassium-titanyl-phosphate lasers, and intense-pulse light devices are also effective in treating persistent erythema but are less effective for transient flushing.
 

Treatment of papules and pustules

For treating papules and pustules, the 2019 systemic review also found high-certainty evidence for using azelaic acid and topical ivermectin, and moderate-certainty evidence for using topical metronidazole and topical minocycline. “Topical ivermectin was demonstrated to be the most effective topical treatment for papulopustular rosacea and to provide the greatest psychological benefit to these patients,” Dr. Graber said.

In a double-blind, multicenter 15-week trial comparing azelaic acid 15% gel with metronidazole 0.75% gel in patients with papulopustular rosacea, both agents were found to be effective. But those treated with azelaic acid 15% gel had a greater reduction in lesion counts and erythema, and improvement in global assessments, compared with metronidazole 0.75% gel. However, the azelaic acid 15% gel was associated with more stinging compared with metronidazole 0.75% gel, although it was usually transient.

Another study, a double-blind, single-center, 15-week trial, compared the efficacy of azelaic acid 20% cream with metronidazole 0.75% cream. Both agents were found to be effective and had similar levels of reductions in papules and pustules. However, patients in the azelaic acid 20% cream arm had significantly higher physician ratings of global improvement, as well as overall higher patient satisfaction.

More recently, a phase 3 study of 962 patients found that ivermectin 1% cream once daily improved quality of life slightly more than metronidazole 0.75% cream twice daily. No difference in adverse events were noted between the two agents.

Other options for treating papules and pustules include topical minocycline 1.5% foam, which is FDA approved for rosacea, as well as second-line agents topical sodium sulfacetamide with sulfur cleanser (cream or lotion), and permethrin, Dr. Graber said.

As for treating papules and pustules with oral agents, the strongest evidence favors oral tetracyclines and isotretinoin, she noted.

Doxycycline, minocycline, tetracycline, and sarecycline can be used as monotherapy or coadministered with topical agents. “The addition of topical agents may also help to shorten the duration of antibiotic use, which is very important,” Dr. Graber said.

She noted that oral beta-blockers might be useful to treat persistent erythema and flushing because they antagonize the effects of sympathetic nerve stimulation and circulating catecholamines at b-adrenoceptors. Carvedilol and propranolol have been the most studied. The most common potential side effects are hypotension and bradycardia.

Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.

MedscapeLive and this news organization are owned by the same parent company.

dbrunk@mdedge.com

In the clinical experience of Emmy Graber, MD, MBA, rosacea is in the eye of the beholder.

“It’s not really up to us as the providers as to what’s important to the patient or how bad their rosacea is,” she said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It really is up to the patient,” added Dr. Graber, president of The Dermatology Institute of Boston, who recommends asking patients about how severe they consider their rosacea to be, and what about rosacea bothers them most. Their responses may be surprising.

A study published in 2017 showed that complete resolution of even mild rosacea prolongs remission of rosacea, and most importantly, improves the quality of life for patients. “So, don’t discount what you consider to be mild rosacea in patients,” she said.

Skin care recommendations

“And don’t forget about basic skin care,” she advised. A recently published Chinese study of 999 rosacea patients and 1,010 controls with healthy skin found that a high frequency of cleansing and expansive use of cleansers were positively correlated with rosacea occurrence, suggesting that overcleansing can be a risk factor for rosacea. “Ask your patient, ‘how often are you cleaning your face?’ ” Dr. Graber suggested. “You might find that they’re overdoing it by washing three or four times a day. Several studies have shown that basic skin care alone improves rosacea.”

Skin care recommendations for patients with rosacea include avoiding chemical or physical exfoliants and alcohol-based topical products, and moisturizing and washing their faces with mild, synthetic detergent-based products rather than traditional soaps, which may further alkalinize and irritate the skin. “Patients should also be counseled to use physical-based sunscreens rather than chemical-based sunscreens,” she said.
 

Treating erythema

For treating erythema with topicals, a systematic review published in 2019 found the most evidence for brimonidine 0.33% gel, an alpha2-adrenergic agonist, and oxymetazoline 1% cream, an alpha1-adrenergic agonist. “Both of these products functionally constrict facial blood vessels,” and are Food and Drug Administration approved for treating persistent erythema, Dr. Graber said. “These products improve erythema within 3 hours of and up to 12 hours after application and overall, they are well tolerated.”

Rosacea.org

Based on clinical trial results, about 15% of patients on brimonidine report adverse reactions such as dermatitis, burning, pruritus, and erythema, compared with 8% of patients on oxymetazoline. At the same time, up to 20% of individuals on brimonidine report rebound erythema, compared with fewer than 1% of those using oxymetazoline. Laser and light therapies such as pulse-dye lasers, potassium-titanyl-phosphate lasers, and intense-pulse light devices are also effective in treating persistent erythema but are less effective for transient flushing.
 

Treatment of papules and pustules

For treating papules and pustules, the 2019 systemic review also found high-certainty evidence for using azelaic acid and topical ivermectin, and moderate-certainty evidence for using topical metronidazole and topical minocycline. “Topical ivermectin was demonstrated to be the most effective topical treatment for papulopustular rosacea and to provide the greatest psychological benefit to these patients,” Dr. Graber said.

In a double-blind, multicenter 15-week trial comparing azelaic acid 15% gel with metronidazole 0.75% gel in patients with papulopustular rosacea, both agents were found to be effective. But those treated with azelaic acid 15% gel had a greater reduction in lesion counts and erythema, and improvement in global assessments, compared with metronidazole 0.75% gel. However, the azelaic acid 15% gel was associated with more stinging compared with metronidazole 0.75% gel, although it was usually transient.

Another study, a double-blind, single-center, 15-week trial, compared the efficacy of azelaic acid 20% cream with metronidazole 0.75% cream. Both agents were found to be effective and had similar levels of reductions in papules and pustules. However, patients in the azelaic acid 20% cream arm had significantly higher physician ratings of global improvement, as well as overall higher patient satisfaction.

More recently, a phase 3 study of 962 patients found that ivermectin 1% cream once daily improved quality of life slightly more than metronidazole 0.75% cream twice daily. No difference in adverse events were noted between the two agents.

Other options for treating papules and pustules include topical minocycline 1.5% foam, which is FDA approved for rosacea, as well as second-line agents topical sodium sulfacetamide with sulfur cleanser (cream or lotion), and permethrin, Dr. Graber said.

As for treating papules and pustules with oral agents, the strongest evidence favors oral tetracyclines and isotretinoin, she noted.

Doxycycline, minocycline, tetracycline, and sarecycline can be used as monotherapy or coadministered with topical agents. “The addition of topical agents may also help to shorten the duration of antibiotic use, which is very important,” Dr. Graber said.

She noted that oral beta-blockers might be useful to treat persistent erythema and flushing because they antagonize the effects of sympathetic nerve stimulation and circulating catecholamines at b-adrenoceptors. Carvedilol and propranolol have been the most studied. The most common potential side effects are hypotension and bradycardia.

Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.

MedscapeLive and this news organization are owned by the same parent company.

dbrunk@mdedge.com

In the clinical experience of Emmy Graber, MD, MBA, rosacea is in the eye of the beholder.

“It’s not really up to us as the providers as to what’s important to the patient or how bad their rosacea is,” she said during MedscapeLive’s annual Las Vegas Dermatology Seminar. “It really is up to the patient,” added Dr. Graber, president of The Dermatology Institute of Boston, who recommends asking patients about how severe they consider their rosacea to be, and what about rosacea bothers them most. Their responses may be surprising.

A study published in 2017 showed that complete resolution of even mild rosacea prolongs remission of rosacea, and most importantly, improves the quality of life for patients. “So, don’t discount what you consider to be mild rosacea in patients,” she said.

Skin care recommendations

“And don’t forget about basic skin care,” she advised. A recently published Chinese study of 999 rosacea patients and 1,010 controls with healthy skin found that a high frequency of cleansing and expansive use of cleansers were positively correlated with rosacea occurrence, suggesting that overcleansing can be a risk factor for rosacea. “Ask your patient, ‘how often are you cleaning your face?’ ” Dr. Graber suggested. “You might find that they’re overdoing it by washing three or four times a day. Several studies have shown that basic skin care alone improves rosacea.”

Skin care recommendations for patients with rosacea include avoiding chemical or physical exfoliants and alcohol-based topical products, and moisturizing and washing their faces with mild, synthetic detergent-based products rather than traditional soaps, which may further alkalinize and irritate the skin. “Patients should also be counseled to use physical-based sunscreens rather than chemical-based sunscreens,” she said.
 

Treating erythema

For treating erythema with topicals, a systematic review published in 2019 found the most evidence for brimonidine 0.33% gel, an alpha2-adrenergic agonist, and oxymetazoline 1% cream, an alpha1-adrenergic agonist. “Both of these products functionally constrict facial blood vessels,” and are Food and Drug Administration approved for treating persistent erythema, Dr. Graber said. “These products improve erythema within 3 hours of and up to 12 hours after application and overall, they are well tolerated.”

Rosacea.org

Based on clinical trial results, about 15% of patients on brimonidine report adverse reactions such as dermatitis, burning, pruritus, and erythema, compared with 8% of patients on oxymetazoline. At the same time, up to 20% of individuals on brimonidine report rebound erythema, compared with fewer than 1% of those using oxymetazoline. Laser and light therapies such as pulse-dye lasers, potassium-titanyl-phosphate lasers, and intense-pulse light devices are also effective in treating persistent erythema but are less effective for transient flushing.
 

Treatment of papules and pustules

For treating papules and pustules, the 2019 systemic review also found high-certainty evidence for using azelaic acid and topical ivermectin, and moderate-certainty evidence for using topical metronidazole and topical minocycline. “Topical ivermectin was demonstrated to be the most effective topical treatment for papulopustular rosacea and to provide the greatest psychological benefit to these patients,” Dr. Graber said.

In a double-blind, multicenter 15-week trial comparing azelaic acid 15% gel with metronidazole 0.75% gel in patients with papulopustular rosacea, both agents were found to be effective. But those treated with azelaic acid 15% gel had a greater reduction in lesion counts and erythema, and improvement in global assessments, compared with metronidazole 0.75% gel. However, the azelaic acid 15% gel was associated with more stinging compared with metronidazole 0.75% gel, although it was usually transient.

Another study, a double-blind, single-center, 15-week trial, compared the efficacy of azelaic acid 20% cream with metronidazole 0.75% cream. Both agents were found to be effective and had similar levels of reductions in papules and pustules. However, patients in the azelaic acid 20% cream arm had significantly higher physician ratings of global improvement, as well as overall higher patient satisfaction.

More recently, a phase 3 study of 962 patients found that ivermectin 1% cream once daily improved quality of life slightly more than metronidazole 0.75% cream twice daily. No difference in adverse events were noted between the two agents.

Other options for treating papules and pustules include topical minocycline 1.5% foam, which is FDA approved for rosacea, as well as second-line agents topical sodium sulfacetamide with sulfur cleanser (cream or lotion), and permethrin, Dr. Graber said.

As for treating papules and pustules with oral agents, the strongest evidence favors oral tetracyclines and isotretinoin, she noted.

Doxycycline, minocycline, tetracycline, and sarecycline can be used as monotherapy or coadministered with topical agents. “The addition of topical agents may also help to shorten the duration of antibiotic use, which is very important,” Dr. Graber said.

She noted that oral beta-blockers might be useful to treat persistent erythema and flushing because they antagonize the effects of sympathetic nerve stimulation and circulating catecholamines at b-adrenoceptors. Carvedilol and propranolol have been the most studied. The most common potential side effects are hypotension and bradycardia.

Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.

MedscapeLive and this news organization are owned by the same parent company.

dbrunk@mdedge.com

A study on the role of the ocular surface microbiome in rosacea pathogenesis and an investigation of elevated intracellular signals in rosacea lesions earned new research funding from the National Rosacea Society (NRS) this year, as part of the organization’s research grants program.

National Rosacea Society

The NRS research grants program was created to increase knowledge and understanding of not only the potential causes of rosacea, but other aspects of the disease that may inform prevention, treatment, or a potential cure, according to the press release announcing the recipients.

New research grant recipient Sezen Karakus, MD, of the Johns Hopkins Wilmer Eye Institute, Baltimore, received $15,000 for a study on the contribution of the ocular surface microbiome to the development of rosacea. Ocular rosacea can result in corneal complications severe enough to affect vision, and identifying the microorganisms on the ocular surface may lead to new treatment strategies, Dr. Karakus said in the release. He will collaborate on this research with dermatologist Noori Kim, MD, of Johns Hopkins University, Baltimore.

A second new research grant went to Emmanuel Contassot, MD, project leader in the dermatology department at of the University Hospital of Basel, Switzerland, who received $5,000 to investigate whether certain elevated intracellular signals in rosacea lesions may promote the skin inflammation that may be a root cause of the condition.

The NRS also renewed its support of a pair of ongoing studies. Michelle Trautwein, MD, of the Institute for Biodiversity Science and Sustainability at the California Academy of Sciences, continues her work on the first study to sequence the genome of Demodex mites; the study also identifies associated bacteria that may play a role in rosacea.

National Rosacea Society

A study on the role of the ocular surface microbiome in rosacea pathogenesis and an investigation of elevated intracellular signals in rosacea lesions earned new research funding from the National Rosacea Society (NRS) this year, as part of the organization’s research grants program.

National Rosacea Society

The NRS research grants program was created to increase knowledge and understanding of not only the potential causes of rosacea, but other aspects of the disease that may inform prevention, treatment, or a potential cure, according to the press release announcing the recipients.

New research grant recipient Sezen Karakus, MD, of the Johns Hopkins Wilmer Eye Institute, Baltimore, received $15,000 for a study on the contribution of the ocular surface microbiome to the development of rosacea. Ocular rosacea can result in corneal complications severe enough to affect vision, and identifying the microorganisms on the ocular surface may lead to new treatment strategies, Dr. Karakus said in the release. He will collaborate on this research with dermatologist Noori Kim, MD, of Johns Hopkins University, Baltimore.

A second new research grant went to Emmanuel Contassot, MD, project leader in the dermatology department at of the University Hospital of Basel, Switzerland, who received $5,000 to investigate whether certain elevated intracellular signals in rosacea lesions may promote the skin inflammation that may be a root cause of the condition.

The NRS also renewed its support of a pair of ongoing studies. Michelle Trautwein, MD, of the Institute for Biodiversity Science and Sustainability at the California Academy of Sciences, continues her work on the first study to sequence the genome of Demodex mites; the study also identifies associated bacteria that may play a role in rosacea.

National Rosacea Society

A study on the role of the ocular surface microbiome in rosacea pathogenesis and an investigation of elevated intracellular signals in rosacea lesions earned new research funding from the National Rosacea Society (NRS) this year, as part of the organization’s research grants program.

National Rosacea Society

The NRS research grants program was created to increase knowledge and understanding of not only the potential causes of rosacea, but other aspects of the disease that may inform prevention, treatment, or a potential cure, according to the press release announcing the recipients.

New research grant recipient Sezen Karakus, MD, of the Johns Hopkins Wilmer Eye Institute, Baltimore, received $15,000 for a study on the contribution of the ocular surface microbiome to the development of rosacea. Ocular rosacea can result in corneal complications severe enough to affect vision, and identifying the microorganisms on the ocular surface may lead to new treatment strategies, Dr. Karakus said in the release. He will collaborate on this research with dermatologist Noori Kim, MD, of Johns Hopkins University, Baltimore.

A second new research grant went to Emmanuel Contassot, MD, project leader in the dermatology department at of the University Hospital of Basel, Switzerland, who received $5,000 to investigate whether certain elevated intracellular signals in rosacea lesions may promote the skin inflammation that may be a root cause of the condition.

The NRS also renewed its support of a pair of ongoing studies. Michelle Trautwein, MD, of the Institute for Biodiversity Science and Sustainability at the California Academy of Sciences, continues her work on the first study to sequence the genome of Demodex mites; the study also identifies associated bacteria that may play a role in rosacea.

National Rosacea Society

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Rosacea fulminans (RF) is a rare facial dermatosis characterized by its fulminating course. ¹ It presents with superficial and deep-seated papules, pustules, and nodules combined with an intense reddish or cyanotic erythema localized to the face. Furthermore, there is an absence of comedones and involvement of the chest or back. ² Rosacea fulminans primarily affects women and often is, but not always, proceeded by seborrhea, chronic acne vulgaris, or rosacea. Although the etiology of RF remains unknown, immunologic, hormonal, and vascular factors have been implicated. ³ We report a case of RF in a pregnant patient with a history of mild acne as a teenager that was long ago resolved.

Case Report

A 32-year-old pregnant woman (10 weeks’ gestation) presented with a rapidly progressing inflammatory disorder of the face of 1 month’s duration. The lesions developed 3 weeks after beginning progesterone therapy (200 mg vaginal suppository) for infertility due to polycystic ovary syndrome. Despite discontinuing progesterone for the last month, the patient’s lesions had dramatically worsened (Figure 1). Empiric cephalosporin treatment prescribed by her primary care physician yielded no improvement. Physical examination at the current presentation revealed erythematous nodules and pustules all over the face, coalescing into large thick plaques on the patient’s right cheek and chin. Submental nodes were palpable and tender. Based on the initial clinical findings, acne conglobata secondary to progesterone therapy was considered. The patient was given intralesional triamcinolone (2.5 mg/cc) injections to all larger nodules and several blue light treatments.

The injected areas had improved 5 days after the initial visit; however, the chin and right paranasal cheek developed even more nodules and papules coalescing into large plaques. After consulting the patient’s obstetrician, prednisone (20 mg once daily) was initiated. Three weeks later, the patient’s nodular lesions had improved, but there was a showering of more than 100 pustules and increased general erythema of the entire face (Figure 2). Crotamiton cream 10% (every day before noon), ivermectin cream 1% (every night at bedtime), and sodium sulfacetamide cleanser 10% once daily were added to the treatment plan.

The patient delivered a healthy girl (birth weight, 1.985 kg) prematurely at 34 weeks’ gestation. At 2 months postpartum, the patient’s existing lesions continued to spontaneously improve; however, she still had numerous nodules and papules and continued to develop new lesions and form additional scars. Isotretinoin was instituted at 3 months postpartum upon cessation of nursing. Three months later (40 mg/d isotretinoin), the patient was nearly clear. At 8 months postpartum, isotretinoin was discontinued after a course of 150 mg/kg.

Comment

Rosacea fulminans initially was called pyoderma faciale but was later regarded as a severe form of rosacea and was renamed rosacea fulminans.² According to a PubMed search of articles indexed for MEDLINE using the terms pregnancy and rosacea fulminans or pyoderma faciale, we identified 12 publications reporting 20 cases of RF associated with pregnancy (Table). Although there is no substantial evidence regarding the exact mechanism, these cases indicate that pregnancy can be an exacerbating or causative factor in the pathogenesis of RF.

In addition to pregnancy, RF has been associated with inflammatory bowel disease, thyroid and liver disease, erythema nodosum, and severe emotional trauma. However, no organism has been consistently isolated, and no evidence of family history has been reported.¹ Histopathologic findings are dependent on the stage of disease. Massive infiltrates of neutrophils may be observed in early stages. In older lesions, infiltrates take the form of epithelioid cell granulomas.²

Treatment of RF during pregnancy is challenging. Early and aggressive treatment with retinoids, tetracycline antibiotics, antiandrogenic contraceptives, and dapsone is recommended in patients who are not pregnant; these therapies are all contraindicated in pregnancy. Topical steroids can be safely used; however, systemic steroids usually are required to control RF. The use of systemic steroids can only be justified if the risks for intrauterine growth retardation, maternal diabetes mellitus, and hypertension outweigh the benefits of treating this severe disfiguring skin condition.¹⁰ A study by Bakar et al¹³ indicated that azithromycin is an effective and safe alternative in the treatment of RF. It has a superior pharmacokinetic profile compared to other macrolides and does not pose increased risks for congenital malformation or miscarriage. Because of the concomitant use of both azithromycin and prednisone, it is not possible to determine which had the larger role in the patient’s improvement.

Isotretinoin therapy in our patient led to substantial improvement of RF. Time will tell if the response will be durable. Also unknown is the risk for recurrence with subsequent pregnancies, which has not been reported in the literature. Although it is difficult to confidently say that pregnancy was the inciting factor in this patient’s RF, this case certainly provides more evidence for a link between pregnancy and RF.

Rosacea fulminans (RF) is a rare facial dermatosis characterized by its fulminating course. ¹ It presents with superficial and deep-seated papules, pustules, and nodules combined with an intense reddish or cyanotic erythema localized to the face. Furthermore, there is an absence of comedones and involvement of the chest or back. ² Rosacea fulminans primarily affects women and often is, but not always, proceeded by seborrhea, chronic acne vulgaris, or rosacea. Although the etiology of RF remains unknown, immunologic, hormonal, and vascular factors have been implicated. ³ We report a case of RF in a pregnant patient with a history of mild acne as a teenager that was long ago resolved.

Case Report

A 32-year-old pregnant woman (10 weeks’ gestation) presented with a rapidly progressing inflammatory disorder of the face of 1 month’s duration. The lesions developed 3 weeks after beginning progesterone therapy (200 mg vaginal suppository) for infertility due to polycystic ovary syndrome. Despite discontinuing progesterone for the last month, the patient’s lesions had dramatically worsened (Figure 1). Empiric cephalosporin treatment prescribed by her primary care physician yielded no improvement. Physical examination at the current presentation revealed erythematous nodules and pustules all over the face, coalescing into large thick plaques on the patient’s right cheek and chin. Submental nodes were palpable and tender. Based on the initial clinical findings, acne conglobata secondary to progesterone therapy was considered. The patient was given intralesional triamcinolone (2.5 mg/cc) injections to all larger nodules and several blue light treatments.

The injected areas had improved 5 days after the initial visit; however, the chin and right paranasal cheek developed even more nodules and papules coalescing into large plaques. After consulting the patient’s obstetrician, prednisone (20 mg once daily) was initiated. Three weeks later, the patient’s nodular lesions had improved, but there was a showering of more than 100 pustules and increased general erythema of the entire face (Figure 2). Crotamiton cream 10% (every day before noon), ivermectin cream 1% (every night at bedtime), and sodium sulfacetamide cleanser 10% once daily were added to the treatment plan.

The patient delivered a healthy girl (birth weight, 1.985 kg) prematurely at 34 weeks’ gestation. At 2 months postpartum, the patient’s existing lesions continued to spontaneously improve; however, she still had numerous nodules and papules and continued to develop new lesions and form additional scars. Isotretinoin was instituted at 3 months postpartum upon cessation of nursing. Three months later (40 mg/d isotretinoin), the patient was nearly clear. At 8 months postpartum, isotretinoin was discontinued after a course of 150 mg/kg.

Comment

Rosacea fulminans initially was called pyoderma faciale but was later regarded as a severe form of rosacea and was renamed rosacea fulminans.² According to a PubMed search of articles indexed for MEDLINE using the terms pregnancy and rosacea fulminans or pyoderma faciale, we identified 12 publications reporting 20 cases of RF associated with pregnancy (Table). Although there is no substantial evidence regarding the exact mechanism, these cases indicate that pregnancy can be an exacerbating or causative factor in the pathogenesis of RF.

In addition to pregnancy, RF has been associated with inflammatory bowel disease, thyroid and liver disease, erythema nodosum, and severe emotional trauma. However, no organism has been consistently isolated, and no evidence of family history has been reported.¹ Histopathologic findings are dependent on the stage of disease. Massive infiltrates of neutrophils may be observed in early stages. In older lesions, infiltrates take the form of epithelioid cell granulomas.²

Treatment of RF during pregnancy is challenging. Early and aggressive treatment with retinoids, tetracycline antibiotics, antiandrogenic contraceptives, and dapsone is recommended in patients who are not pregnant; these therapies are all contraindicated in pregnancy. Topical steroids can be safely used; however, systemic steroids usually are required to control RF. The use of systemic steroids can only be justified if the risks for intrauterine growth retardation, maternal diabetes mellitus, and hypertension outweigh the benefits of treating this severe disfiguring skin condition.¹⁰ A study by Bakar et al¹³ indicated that azithromycin is an effective and safe alternative in the treatment of RF. It has a superior pharmacokinetic profile compared to other macrolides and does not pose increased risks for congenital malformation or miscarriage. Because of the concomitant use of both azithromycin and prednisone, it is not possible to determine which had the larger role in the patient’s improvement.

Isotretinoin therapy in our patient led to substantial improvement of RF. Time will tell if the response will be durable. Also unknown is the risk for recurrence with subsequent pregnancies, which has not been reported in the literature. Although it is difficult to confidently say that pregnancy was the inciting factor in this patient’s RF, this case certainly provides more evidence for a link between pregnancy and RF.

Rosacea fulminans (RF) is a rare facial dermatosis characterized by its fulminating course. ¹ It presents with superficial and deep-seated papules, pustules, and nodules combined with an intense reddish or cyanotic erythema localized to the face. Furthermore, there is an absence of comedones and involvement of the chest or back. ² Rosacea fulminans primarily affects women and often is, but not always, proceeded by seborrhea, chronic acne vulgaris, or rosacea. Although the etiology of RF remains unknown, immunologic, hormonal, and vascular factors have been implicated. ³ We report a case of RF in a pregnant patient with a history of mild acne as a teenager that was long ago resolved.

Case Report

A 32-year-old pregnant woman (10 weeks’ gestation) presented with a rapidly progressing inflammatory disorder of the face of 1 month’s duration. The lesions developed 3 weeks after beginning progesterone therapy (200 mg vaginal suppository) for infertility due to polycystic ovary syndrome. Despite discontinuing progesterone for the last month, the patient’s lesions had dramatically worsened (Figure 1). Empiric cephalosporin treatment prescribed by her primary care physician yielded no improvement. Physical examination at the current presentation revealed erythematous nodules and pustules all over the face, coalescing into large thick plaques on the patient’s right cheek and chin. Submental nodes were palpable and tender. Based on the initial clinical findings, acne conglobata secondary to progesterone therapy was considered. The patient was given intralesional triamcinolone (2.5 mg/cc) injections to all larger nodules and several blue light treatments.

The injected areas had improved 5 days after the initial visit; however, the chin and right paranasal cheek developed even more nodules and papules coalescing into large plaques. After consulting the patient’s obstetrician, prednisone (20 mg once daily) was initiated. Three weeks later, the patient’s nodular lesions had improved, but there was a showering of more than 100 pustules and increased general erythema of the entire face (Figure 2). Crotamiton cream 10% (every day before noon), ivermectin cream 1% (every night at bedtime), and sodium sulfacetamide cleanser 10% once daily were added to the treatment plan.

The patient delivered a healthy girl (birth weight, 1.985 kg) prematurely at 34 weeks’ gestation. At 2 months postpartum, the patient’s existing lesions continued to spontaneously improve; however, she still had numerous nodules and papules and continued to develop new lesions and form additional scars. Isotretinoin was instituted at 3 months postpartum upon cessation of nursing. Three months later (40 mg/d isotretinoin), the patient was nearly clear. At 8 months postpartum, isotretinoin was discontinued after a course of 150 mg/kg.

Comment

Rosacea fulminans initially was called pyoderma faciale but was later regarded as a severe form of rosacea and was renamed rosacea fulminans.² According to a PubMed search of articles indexed for MEDLINE using the terms pregnancy and rosacea fulminans or pyoderma faciale, we identified 12 publications reporting 20 cases of RF associated with pregnancy (Table). Although there is no substantial evidence regarding the exact mechanism, these cases indicate that pregnancy can be an exacerbating or causative factor in the pathogenesis of RF.

In addition to pregnancy, RF has been associated with inflammatory bowel disease, thyroid and liver disease, erythema nodosum, and severe emotional trauma. However, no organism has been consistently isolated, and no evidence of family history has been reported.¹ Histopathologic findings are dependent on the stage of disease. Massive infiltrates of neutrophils may be observed in early stages. In older lesions, infiltrates take the form of epithelioid cell granulomas.²

Treatment of RF during pregnancy is challenging. Early and aggressive treatment with retinoids, tetracycline antibiotics, antiandrogenic contraceptives, and dapsone is recommended in patients who are not pregnant; these therapies are all contraindicated in pregnancy. Topical steroids can be safely used; however, systemic steroids usually are required to control RF. The use of systemic steroids can only be justified if the risks for intrauterine growth retardation, maternal diabetes mellitus, and hypertension outweigh the benefits of treating this severe disfiguring skin condition.¹⁰ A study by Bakar et al¹³ indicated that azithromycin is an effective and safe alternative in the treatment of RF. It has a superior pharmacokinetic profile compared to other macrolides and does not pose increased risks for congenital malformation or miscarriage. Because of the concomitant use of both azithromycin and prednisone, it is not possible to determine which had the larger role in the patient’s improvement.

Isotretinoin therapy in our patient led to substantial improvement of RF. Time will tell if the response will be durable. Also unknown is the risk for recurrence with subsequent pregnancies, which has not been reported in the literature. Although it is difficult to confidently say that pregnancy was the inciting factor in this patient’s RF, this case certainly provides more evidence for a link between pregnancy and RF.

Acne & Rosacea

• Rosacea phenotypes
• Erythema and flushing
• Aggressive treatment of acne
• Energy-based rosacea therapy
• Diet and acne

Acne & Rosacea

• Rosacea phenotypes
• Erythema and flushing
• Aggressive treatment of acne
• Energy-based rosacea therapy
• Diet and acne

Acne & Rosacea

• Rosacea phenotypes
• Erythema and flushing
• Aggressive treatment of acne
• Energy-based rosacea therapy
• Diet and acne

Acne rosacea is a chronic inflammatory disease that may affect the facial skin, eyes, and eyelids.¹ It is characterized by transient or persistent flushing, facial erythema, and telangiectases, generally located on the central portion of the face, and may progress to papules and pustules.^2,3 At the late stage of the disease, dermal edema or fibroplasia and sebaceous gland hypertrophy may cause phymatous alterations in the skin. In 2004, the National Rosacea Society Expert Committee developed a classification system for rosacea to standardize subtypes and variants that has since been widely accepted and continues to aid in research and epidemiologic studies.⁴ The committee defined 4 subtypes based on clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular rosacea.^2,3

Ocular rosacea may accompany mild, moderate, and severe dermatologic disease or may occur in the absence of diagnostic skin disease.⁵ Ocular signs include eyelid margin telangiectasia, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Common symptoms include burning, stinging, light sensitivity, and foreign-body sensation. Ocular signs commonly seen in rosacea are meibomian gland dysfunction characterized by inspissation and inflammation of the meibomian glands (chalazia), conjunctivitis, honey crust and cylindrical collarette accumulation at the base of the eyelashes, irregularity of the eyelid margin architecture, and evaporative tear dysfunction.^5,6

The physiopathology of rosacea is still unknown. Potential factors include genetic predisposition, abnormal inflammation, vascular dysfunction, and involvement of several microbial agents, such as commensal Demodex mites. The number of Demodex mites on normal skin flora is less than 5/cm²; however, the increased vascular dilation and capillary permeability associated with rosacea that result from sunlight and heat exposure increase the density of Demodex folliculorum.⁷ Elevated Demodex mite density has been observed in the lumens of the sebaceous follicles in patients with rosacea. However, because the severity of the clinical manifestations of the disease is not directly associated with the density of D folliculorum, it generally is accepted that D folliculorum is not a pathogenetic but rather an exacerbating factor.⁸ It has been reported that this species of mite is mostly found on the face and around the eyelashes and scalp of patients and that it can cause ocular surface inflammation.⁸

Most studies have researched ocular manifestations of rosacea but not ocular involvement in rosacea patients with and without Demodex mite infestation. In our study, we sought to compare the ocular surface, meibomian gland characteristics, and tear film abnormalities among patients with cutaneous rosacea with and without Demodex infestation.

Materials and Methods

We conducted a retrospective study of 60 patients with cutaneous rosacea. This study was approved by the ethics committee of the local hospital (2018/002-003), and all patients provided verbal and written informed consent before participating in the study. The study was carried out according to the guidelines of the Declaration of Helsinki.

Patient Selection and Evaluation
Patients diagnosed with rosacea by a dermatologist within 6 months were included in the study. Diagnosis of the disease was made after a detailed anamnesis and dermatologic examination. Rosacea was diagnosed if patients had an itching sensation, erythema and/or erythema attacks, and papules and pustules, and fulfilled the diagnostic criteria according to the National Rosacea Society. The skin disease was classified according to the subtypes as ETR, PPR, phymatous rosacea, or ocular rosacea.

The standard skin surface biopsy method was used in 60 patients for detecting Demodex density. When more than 5 mites were detected per square centimeter, the result was recorded as positive. Thirty consecutive, newly diagnosed patients with cutaneous acne rosacea with Demodex infestation and 30 consecutive, newly diagnosed sex- and age-matched patients with acne rosacea without Demodex infestation admitted to the dermatology outpatient clinic were included to this study. The patients who did not have any known dermatologic, systemic, or ocular diseases were included in the study. Patients who met any of the following criteria were excluded from the study: prior anti-inflammatory topical and/or systemic treatment for rosacea during the last 3 months, contact lens wear, eyelid surgery, or autoimmune disease requiring treatment.

Microscopic Demodex Examination
Demodex count was determined using a standardized skin surface biopsy, which is a noninvasive method. Every patient gave samples from the cheeks. This biopsy was repeated from the same site. A drop of cyanoacrylate was placed on a clean slide, pressed against a skin lesion, held in place for 1 minute, and removed. The obtained samples were evaluated under a light microscope (Nikon E200) with oil immersion. When more than 5 mites were detected per square centimeter, the result was recorded as positive.

Ophthalmologic Examination
A complete ophthalmologic examination including visual acuity assessment, standardized slit lamp examination, and fundus examination was done for all patients. Ocular rosacea was diagnosed on detection of 1 or more of the following: watery or bloodshot appearance, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and eyelid margin, eyelid lid and periocular erythema, anterior blepharitis, meibomian gland dysfunction, or irregularity of eyelid margins. All patients were screened for the signs and symptoms of ocular rosacea and underwent other ophthalmologic examinations, including tear function tests. Tear functions were evaluated with Schirmer tests without anesthesia and fluorescein tear breakup time (TBUT). Tear film breakup time was assessed after instillation of 2% fluorescein staining under a cobalt blue filter. The time interval between the last complete blink and the appearance of the first dry spot was recorded. The mean of 3 consecutive measurements was obtained. The Schirmer test was performed without topical anesthesia using a standardized filter strip (Bio-Tech Vision Care). The amount of wetting was measured after 5 minutes. Meibomian gland expressibility was assessed by applying digital pressure to the eyelid margin.

Statistical Analysis
Statistical analysis of the study was performed with SPSS Statistics Version 22.0 (SPSS Inc). Continuous variables were reported as mean (SD), and categorical variables were reported as percentages and counts. Descriptive statistics for numerical variables were created. An independent sample t test was used for normally distributed continuous variables. The Kolmogorov-Smirnov test was used to determine normality. The Schirmer test without anesthesia and TBUT values among groups were compared using one-way analysis of variance. The differences were calculated using the multiple comparison Tukey test. P<.05 was considered statistically significant.

Results

Demographic Characteristics of Rosacea Patients
Sixty eyes of 30 newly diagnosed patients with acne rosacea with Demodex infestation and 60 eyes of 30 newly diagnosed patients with acne rosacea without Demodex infestation were enrolled in this study. The mean age (SD) of the 60 patients was 37.63 (10.01) years. The mean TBUT (SD) of the 120 eyes was 6.65 (3.44) seconds, and the mean Schirmer score (SD) was 12.59 (6.71) mm (Table 1).

Meibomian Gland Dysfunction vs Subgroup of Rosacea Patients
Thirty-four (57%) patients had blepharitis, and 18 (30%) patients had meibomitis. Thirty-five (58.3%) patients had ETR, 5 (8.3%) patients had phymatous rosacea, and 20 (33.4%) patients had PPR (Table 2). Of the Demodex-negative patients, 73.3% (22/30) had ETR, 20% (6/30) had PPR, and 6.7% (2/30) had phymatous rosacea. Of the Demodex-positive patients, 43.3% (13/30) had ETR, 46.7% (14/30) had PPR, and 10% (3/30) had phymatous rosacea (Table 3). Papulopustular rosacea was found to be significantly associated with Demodex positivity (P=.003); neither ETR nor phymatous rosacea was found to be significantly associated with Demodex infestation (P=.66 and P=.13, respectively)(Table 3).

Sixteen (53.3%) patients (32 eyes) in the Demodex-negative group and 21 (70%) patients (42 eyes) in the Demodex-positive group had TBUT values less than 10 seconds. Eighteen (60%) patients (36 eyes) in the Demodex-negative group and 25 (83.3%) patients (50 eyes) in the Demodex-positive group had Schirmer scores less than 10 mm (Table 3). The 2 groups were not significantly different in dry eye findings (P=.25 and P=.29, respectively).

Comment

Inflammation in Rosacea
It is known that the density of nonfloral bacteria as well as D folliculorum and Demodex brevis increases in skin affected by rosacea compared to normal skin. Vascular dilation associated with rosacea that results from sunlight and heat causes increased capillary permeability and creates the ideal environment for the proliferation of D folliculorum. Demodex is thought to act as a vector for the activity of certain other microorganisms, particularly Bacillus oleronius, and thus initiates the inflammatory response associated with rosacea.⁹

One study reported that the inflammation associated with rosacea that was caused by Demodex and other environmental stimuli occurred through toll-like receptor 2 and various cytokines.¹⁰ It has been reported that the abnormal function of toll-like receptor 2 in the epidermis leads to the increased production of cathelicidin. Cathelicidin is an antimicrobial peptide with both vasoactive and proinflammatory activity and has been used as a basis to explain the pathogenesis of facial erythema, flushing, and telangiectasia in the context of rosacea.^11,12 In addition, it has been reported that the increased secretion of proinflammatory cytokines such as IL-1 and gelatinase B in ocular rosacea leads to tearing film abnormalities that result from increased bacterial flora in the eyelids, which subsequently leads to decreased tear drainage and dry eyes.¹³ In addition, B oleronius isolated from a D folliculorum mite from patients with PPR produced proteins that induced an inflammatory immune response in 73% (16/22) of patients with rosacea.¹⁴

Ocular Findings in Rosacea Patients
In our study, PPR was found to be significantly associated with Demodex positivity compared to ETR and phymatous rosacea (P=.003). However, ocular inflammation findings such as blepharitis and meibomitis were not significantly different between Demodex-positive and Demodex-negative patients. Although the mean Schirmer score of Demodex-positive patients was lower than Demodex-negative patients, this difference was not statistically significant. We evaluated a TBUT of less than 10 seconds and a Schirmer score less than 10 mm as dry eye. Accordingly, the number of patients with dry eye was higher in the Demodex-positive group, but this difference was not statistically significant.

Chronic blepharitis, conjunctival inflammation, and meibomian gland dysfunction are among the most common findings of ocular rosacea.^15,16 Patients with ocular rosacea commonly have dry eye and abnormal TBUT and Schirmer scores.¹⁷ In our study, we found that the fluorescein TBUT and Schirmer scores were more likely to be abnormal in the Demodex-positive group, but the difference between the 2 groups was not statistically significant.

It has been reported that proinflammatory cytokines due to a weakened immune system in rosacea patients were increased. The weakened immune system was further supported by the increased concentrations of proinflammatory cytokines such as IL-1 and matrix metalloproteinase 9 in these patients’ tears and the improvement of symptoms after the inhibition of these cytokines.¹¹ Luo et al¹⁸ reported that Demodex inflammation causes dry eye, particularly with D brevis. Ayyildiz and Sezgin¹⁹ reported that Schirmer scores were significantly lower and that the Ocular Surface Disease Index had significantly increased in the Demodex-positive group compared to the Demodex-negative group (P=.001 for both). A Korean study reported that Demodex density was correlated with age, sex, and TBUT results, but there was no significant relationship between Demodex density and Schirmer scores.¹⁶

Sobolewska et al²⁰ administered ivermectin cream 1% to 10 patients with cutaneous and ocular rosacea, but only to the forehead, chin, nose, cheeks, and regions close to the eyelids, and observed a significant improvement in blepharitis (P=.004). They stated that ivermectin, as applied only to the face, suppressed the proinflammatory cytokines associated with rosacea and showed anti-inflammatory effects by reducing Demodex mites.²⁰Li et al²¹ demonstrated a strong correlation between ocular Demodex inflammation and serum reactivity to these bacterial proteins in patients with ocular rosacea, and they found that eyelid margin inflammation and facial rosacea correlated with reactivity to these proteins. These studies suggest a possible role for Demodex infestation and bacterial proteins in the etiology of rosacea.

Gonzalez-Hinojosa et al²² demonstrated that even though eyelash blepharitis was more common in PPR than ETR, there was no statistically significant association between rosacea and Demodex blepharitis. In our study, we found a significant correlation between PPR and Demodex positivity. Also, meibomian gland dysfunction was more common in the Demodex-positive group; however, this result was not statistically significant. One study compared patients with primary demodicosis and patients with rosacea with Demodex-induced blepharitis to healthy controls and found that patients with primary demodicosis and patients with rosacea did not have significantly different ocular findings.²³ In contrast, Forton and De Maertelaer²⁴ reported that patients with PPR had significantly more severe ocular manifestations compared with patients with demodicosis (P=.004).

Mizuno et al²⁵ compared the normal (nonrosacea) population with and without Demodex-infested eyelashes and found that the 2 groups were not significantly different for meibomian gland dysfunction, fluorescein TBUT, or ocular surface discomfort.

Varying results have been reported regarding the association between Demodex and blepharitis or ocular surface discomfort with or without rosacea. In our study, we found that Demodex did not affect tear function tests or meibomian gland function in patients with rosacea. We believe this study is important because it demonstrates the effects of Demodex on ocular findings in patients with cutaneous rosacea.

Limitations
Our study has some limitations. The number of patients was relatively small, resulting in few significant differences between the comparison groups. A larger prospective research study is required to assess the prevalence of Demodex mites in the ocular rosacea population along with associated symptoms and findings.

Conclusion

Rosacea is a chronic disease associated with skin and ocular manifestations that range from mild to severe, that progresses in the form of attacks, and that requires long-term follow-up and treatment. Rosacea most often presents as a disease that causes ocular surface inflammation of varying degrees. Demodex infestation may increase cutaneous or ocular inflammation in rosacea. Therefore, every patient diagnosed with rosacea should be given a dermatologic examination to determine Demodex positivity and an ophthalmologic examination to determine ocular manifestations.

Acne rosacea is a chronic inflammatory disease that may affect the facial skin, eyes, and eyelids.¹ It is characterized by transient or persistent flushing, facial erythema, and telangiectases, generally located on the central portion of the face, and may progress to papules and pustules.^2,3 At the late stage of the disease, dermal edema or fibroplasia and sebaceous gland hypertrophy may cause phymatous alterations in the skin. In 2004, the National Rosacea Society Expert Committee developed a classification system for rosacea to standardize subtypes and variants that has since been widely accepted and continues to aid in research and epidemiologic studies.⁴ The committee defined 4 subtypes based on clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular rosacea.^2,3

Ocular rosacea may accompany mild, moderate, and severe dermatologic disease or may occur in the absence of diagnostic skin disease.⁵ Ocular signs include eyelid margin telangiectasia, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Common symptoms include burning, stinging, light sensitivity, and foreign-body sensation. Ocular signs commonly seen in rosacea are meibomian gland dysfunction characterized by inspissation and inflammation of the meibomian glands (chalazia), conjunctivitis, honey crust and cylindrical collarette accumulation at the base of the eyelashes, irregularity of the eyelid margin architecture, and evaporative tear dysfunction.^5,6

The physiopathology of rosacea is still unknown. Potential factors include genetic predisposition, abnormal inflammation, vascular dysfunction, and involvement of several microbial agents, such as commensal Demodex mites. The number of Demodex mites on normal skin flora is less than 5/cm²; however, the increased vascular dilation and capillary permeability associated with rosacea that result from sunlight and heat exposure increase the density of Demodex folliculorum.⁷ Elevated Demodex mite density has been observed in the lumens of the sebaceous follicles in patients with rosacea. However, because the severity of the clinical manifestations of the disease is not directly associated with the density of D folliculorum, it generally is accepted that D folliculorum is not a pathogenetic but rather an exacerbating factor.⁸ It has been reported that this species of mite is mostly found on the face and around the eyelashes and scalp of patients and that it can cause ocular surface inflammation.⁸

Most studies have researched ocular manifestations of rosacea but not ocular involvement in rosacea patients with and without Demodex mite infestation. In our study, we sought to compare the ocular surface, meibomian gland characteristics, and tear film abnormalities among patients with cutaneous rosacea with and without Demodex infestation.

Materials and Methods

We conducted a retrospective study of 60 patients with cutaneous rosacea. This study was approved by the ethics committee of the local hospital (2018/002-003), and all patients provided verbal and written informed consent before participating in the study. The study was carried out according to the guidelines of the Declaration of Helsinki.

Patient Selection and Evaluation
Patients diagnosed with rosacea by a dermatologist within 6 months were included in the study. Diagnosis of the disease was made after a detailed anamnesis and dermatologic examination. Rosacea was diagnosed if patients had an itching sensation, erythema and/or erythema attacks, and papules and pustules, and fulfilled the diagnostic criteria according to the National Rosacea Society. The skin disease was classified according to the subtypes as ETR, PPR, phymatous rosacea, or ocular rosacea.

The standard skin surface biopsy method was used in 60 patients for detecting Demodex density. When more than 5 mites were detected per square centimeter, the result was recorded as positive. Thirty consecutive, newly diagnosed patients with cutaneous acne rosacea with Demodex infestation and 30 consecutive, newly diagnosed sex- and age-matched patients with acne rosacea without Demodex infestation admitted to the dermatology outpatient clinic were included to this study. The patients who did not have any known dermatologic, systemic, or ocular diseases were included in the study. Patients who met any of the following criteria were excluded from the study: prior anti-inflammatory topical and/or systemic treatment for rosacea during the last 3 months, contact lens wear, eyelid surgery, or autoimmune disease requiring treatment.

Microscopic Demodex Examination
Demodex count was determined using a standardized skin surface biopsy, which is a noninvasive method. Every patient gave samples from the cheeks. This biopsy was repeated from the same site. A drop of cyanoacrylate was placed on a clean slide, pressed against a skin lesion, held in place for 1 minute, and removed. The obtained samples were evaluated under a light microscope (Nikon E200) with oil immersion. When more than 5 mites were detected per square centimeter, the result was recorded as positive.

Ophthalmologic Examination
A complete ophthalmologic examination including visual acuity assessment, standardized slit lamp examination, and fundus examination was done for all patients. Ocular rosacea was diagnosed on detection of 1 or more of the following: watery or bloodshot appearance, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and eyelid margin, eyelid lid and periocular erythema, anterior blepharitis, meibomian gland dysfunction, or irregularity of eyelid margins. All patients were screened for the signs and symptoms of ocular rosacea and underwent other ophthalmologic examinations, including tear function tests. Tear functions were evaluated with Schirmer tests without anesthesia and fluorescein tear breakup time (TBUT). Tear film breakup time was assessed after instillation of 2% fluorescein staining under a cobalt blue filter. The time interval between the last complete blink and the appearance of the first dry spot was recorded. The mean of 3 consecutive measurements was obtained. The Schirmer test was performed without topical anesthesia using a standardized filter strip (Bio-Tech Vision Care). The amount of wetting was measured after 5 minutes. Meibomian gland expressibility was assessed by applying digital pressure to the eyelid margin.

Statistical Analysis
Statistical analysis of the study was performed with SPSS Statistics Version 22.0 (SPSS Inc). Continuous variables were reported as mean (SD), and categorical variables were reported as percentages and counts. Descriptive statistics for numerical variables were created. An independent sample t test was used for normally distributed continuous variables. The Kolmogorov-Smirnov test was used to determine normality. The Schirmer test without anesthesia and TBUT values among groups were compared using one-way analysis of variance. The differences were calculated using the multiple comparison Tukey test. P<.05 was considered statistically significant.

Results

Demographic Characteristics of Rosacea Patients
Sixty eyes of 30 newly diagnosed patients with acne rosacea with Demodex infestation and 60 eyes of 30 newly diagnosed patients with acne rosacea without Demodex infestation were enrolled in this study. The mean age (SD) of the 60 patients was 37.63 (10.01) years. The mean TBUT (SD) of the 120 eyes was 6.65 (3.44) seconds, and the mean Schirmer score (SD) was 12.59 (6.71) mm (Table 1).

Meibomian Gland Dysfunction vs Subgroup of Rosacea Patients
Thirty-four (57%) patients had blepharitis, and 18 (30%) patients had meibomitis. Thirty-five (58.3%) patients had ETR, 5 (8.3%) patients had phymatous rosacea, and 20 (33.4%) patients had PPR (Table 2). Of the Demodex-negative patients, 73.3% (22/30) had ETR, 20% (6/30) had PPR, and 6.7% (2/30) had phymatous rosacea. Of the Demodex-positive patients, 43.3% (13/30) had ETR, 46.7% (14/30) had PPR, and 10% (3/30) had phymatous rosacea (Table 3). Papulopustular rosacea was found to be significantly associated with Demodex positivity (P=.003); neither ETR nor phymatous rosacea was found to be significantly associated with Demodex infestation (P=.66 and P=.13, respectively)(Table 3).

Sixteen (53.3%) patients (32 eyes) in the Demodex-negative group and 21 (70%) patients (42 eyes) in the Demodex-positive group had TBUT values less than 10 seconds. Eighteen (60%) patients (36 eyes) in the Demodex-negative group and 25 (83.3%) patients (50 eyes) in the Demodex-positive group had Schirmer scores less than 10 mm (Table 3). The 2 groups were not significantly different in dry eye findings (P=.25 and P=.29, respectively).

Comment

Inflammation in Rosacea
It is known that the density of nonfloral bacteria as well as D folliculorum and Demodex brevis increases in skin affected by rosacea compared to normal skin. Vascular dilation associated with rosacea that results from sunlight and heat causes increased capillary permeability and creates the ideal environment for the proliferation of D folliculorum. Demodex is thought to act as a vector for the activity of certain other microorganisms, particularly Bacillus oleronius, and thus initiates the inflammatory response associated with rosacea.⁹

One study reported that the inflammation associated with rosacea that was caused by Demodex and other environmental stimuli occurred through toll-like receptor 2 and various cytokines.¹⁰ It has been reported that the abnormal function of toll-like receptor 2 in the epidermis leads to the increased production of cathelicidin. Cathelicidin is an antimicrobial peptide with both vasoactive and proinflammatory activity and has been used as a basis to explain the pathogenesis of facial erythema, flushing, and telangiectasia in the context of rosacea.^11,12 In addition, it has been reported that the increased secretion of proinflammatory cytokines such as IL-1 and gelatinase B in ocular rosacea leads to tearing film abnormalities that result from increased bacterial flora in the eyelids, which subsequently leads to decreased tear drainage and dry eyes.¹³ In addition, B oleronius isolated from a D folliculorum mite from patients with PPR produced proteins that induced an inflammatory immune response in 73% (16/22) of patients with rosacea.¹⁴

Ocular Findings in Rosacea Patients
In our study, PPR was found to be significantly associated with Demodex positivity compared to ETR and phymatous rosacea (P=.003). However, ocular inflammation findings such as blepharitis and meibomitis were not significantly different between Demodex-positive and Demodex-negative patients. Although the mean Schirmer score of Demodex-positive patients was lower than Demodex-negative patients, this difference was not statistically significant. We evaluated a TBUT of less than 10 seconds and a Schirmer score less than 10 mm as dry eye. Accordingly, the number of patients with dry eye was higher in the Demodex-positive group, but this difference was not statistically significant.

Chronic blepharitis, conjunctival inflammation, and meibomian gland dysfunction are among the most common findings of ocular rosacea.^15,16 Patients with ocular rosacea commonly have dry eye and abnormal TBUT and Schirmer scores.¹⁷ In our study, we found that the fluorescein TBUT and Schirmer scores were more likely to be abnormal in the Demodex-positive group, but the difference between the 2 groups was not statistically significant.

It has been reported that proinflammatory cytokines due to a weakened immune system in rosacea patients were increased. The weakened immune system was further supported by the increased concentrations of proinflammatory cytokines such as IL-1 and matrix metalloproteinase 9 in these patients’ tears and the improvement of symptoms after the inhibition of these cytokines.¹¹ Luo et al¹⁸ reported that Demodex inflammation causes dry eye, particularly with D brevis. Ayyildiz and Sezgin¹⁹ reported that Schirmer scores were significantly lower and that the Ocular Surface Disease Index had significantly increased in the Demodex-positive group compared to the Demodex-negative group (P=.001 for both). A Korean study reported that Demodex density was correlated with age, sex, and TBUT results, but there was no significant relationship between Demodex density and Schirmer scores.¹⁶

Sobolewska et al²⁰ administered ivermectin cream 1% to 10 patients with cutaneous and ocular rosacea, but only to the forehead, chin, nose, cheeks, and regions close to the eyelids, and observed a significant improvement in blepharitis (P=.004). They stated that ivermectin, as applied only to the face, suppressed the proinflammatory cytokines associated with rosacea and showed anti-inflammatory effects by reducing Demodex mites.²⁰Li et al²¹ demonstrated a strong correlation between ocular Demodex inflammation and serum reactivity to these bacterial proteins in patients with ocular rosacea, and they found that eyelid margin inflammation and facial rosacea correlated with reactivity to these proteins. These studies suggest a possible role for Demodex infestation and bacterial proteins in the etiology of rosacea.

Gonzalez-Hinojosa et al²² demonstrated that even though eyelash blepharitis was more common in PPR than ETR, there was no statistically significant association between rosacea and Demodex blepharitis. In our study, we found a significant correlation between PPR and Demodex positivity. Also, meibomian gland dysfunction was more common in the Demodex-positive group; however, this result was not statistically significant. One study compared patients with primary demodicosis and patients with rosacea with Demodex-induced blepharitis to healthy controls and found that patients with primary demodicosis and patients with rosacea did not have significantly different ocular findings.²³ In contrast, Forton and De Maertelaer²⁴ reported that patients with PPR had significantly more severe ocular manifestations compared with patients with demodicosis (P=.004).

Mizuno et al²⁵ compared the normal (nonrosacea) population with and without Demodex-infested eyelashes and found that the 2 groups were not significantly different for meibomian gland dysfunction, fluorescein TBUT, or ocular surface discomfort.

Varying results have been reported regarding the association between Demodex and blepharitis or ocular surface discomfort with or without rosacea. In our study, we found that Demodex did not affect tear function tests or meibomian gland function in patients with rosacea. We believe this study is important because it demonstrates the effects of Demodex on ocular findings in patients with cutaneous rosacea.

Limitations
Our study has some limitations. The number of patients was relatively small, resulting in few significant differences between the comparison groups. A larger prospective research study is required to assess the prevalence of Demodex mites in the ocular rosacea population along with associated symptoms and findings.

Conclusion

Rosacea is a chronic disease associated with skin and ocular manifestations that range from mild to severe, that progresses in the form of attacks, and that requires long-term follow-up and treatment. Rosacea most often presents as a disease that causes ocular surface inflammation of varying degrees. Demodex infestation may increase cutaneous or ocular inflammation in rosacea. Therefore, every patient diagnosed with rosacea should be given a dermatologic examination to determine Demodex positivity and an ophthalmologic examination to determine ocular manifestations.

Acne rosacea is a chronic inflammatory disease that may affect the facial skin, eyes, and eyelids.¹ It is characterized by transient or persistent flushing, facial erythema, and telangiectases, generally located on the central portion of the face, and may progress to papules and pustules.^2,3 At the late stage of the disease, dermal edema or fibroplasia and sebaceous gland hypertrophy may cause phymatous alterations in the skin. In 2004, the National Rosacea Society Expert Committee developed a classification system for rosacea to standardize subtypes and variants that has since been widely accepted and continues to aid in research and epidemiologic studies.⁴ The committee defined 4 subtypes based on clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular rosacea.^2,3

Ocular rosacea may accompany mild, moderate, and severe dermatologic disease or may occur in the absence of diagnostic skin disease.⁵ Ocular signs include eyelid margin telangiectasia, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Common symptoms include burning, stinging, light sensitivity, and foreign-body sensation. Ocular signs commonly seen in rosacea are meibomian gland dysfunction characterized by inspissation and inflammation of the meibomian glands (chalazia), conjunctivitis, honey crust and cylindrical collarette accumulation at the base of the eyelashes, irregularity of the eyelid margin architecture, and evaporative tear dysfunction.^5,6

The physiopathology of rosacea is still unknown. Potential factors include genetic predisposition, abnormal inflammation, vascular dysfunction, and involvement of several microbial agents, such as commensal Demodex mites. The number of Demodex mites on normal skin flora is less than 5/cm²; however, the increased vascular dilation and capillary permeability associated with rosacea that result from sunlight and heat exposure increase the density of Demodex folliculorum.⁷ Elevated Demodex mite density has been observed in the lumens of the sebaceous follicles in patients with rosacea. However, because the severity of the clinical manifestations of the disease is not directly associated with the density of D folliculorum, it generally is accepted that D folliculorum is not a pathogenetic but rather an exacerbating factor.⁸ It has been reported that this species of mite is mostly found on the face and around the eyelashes and scalp of patients and that it can cause ocular surface inflammation.⁸

Most studies have researched ocular manifestations of rosacea but not ocular involvement in rosacea patients with and without Demodex mite infestation. In our study, we sought to compare the ocular surface, meibomian gland characteristics, and tear film abnormalities among patients with cutaneous rosacea with and without Demodex infestation.

Materials and Methods

We conducted a retrospective study of 60 patients with cutaneous rosacea. This study was approved by the ethics committee of the local hospital (2018/002-003), and all patients provided verbal and written informed consent before participating in the study. The study was carried out according to the guidelines of the Declaration of Helsinki.

Patient Selection and Evaluation
Patients diagnosed with rosacea by a dermatologist within 6 months were included in the study. Diagnosis of the disease was made after a detailed anamnesis and dermatologic examination. Rosacea was diagnosed if patients had an itching sensation, erythema and/or erythema attacks, and papules and pustules, and fulfilled the diagnostic criteria according to the National Rosacea Society. The skin disease was classified according to the subtypes as ETR, PPR, phymatous rosacea, or ocular rosacea.

The standard skin surface biopsy method was used in 60 patients for detecting Demodex density. When more than 5 mites were detected per square centimeter, the result was recorded as positive. Thirty consecutive, newly diagnosed patients with cutaneous acne rosacea with Demodex infestation and 30 consecutive, newly diagnosed sex- and age-matched patients with acne rosacea without Demodex infestation admitted to the dermatology outpatient clinic were included to this study. The patients who did not have any known dermatologic, systemic, or ocular diseases were included in the study. Patients who met any of the following criteria were excluded from the study: prior anti-inflammatory topical and/or systemic treatment for rosacea during the last 3 months, contact lens wear, eyelid surgery, or autoimmune disease requiring treatment.

Microscopic Demodex Examination
Demodex count was determined using a standardized skin surface biopsy, which is a noninvasive method. Every patient gave samples from the cheeks. This biopsy was repeated from the same site. A drop of cyanoacrylate was placed on a clean slide, pressed against a skin lesion, held in place for 1 minute, and removed. The obtained samples were evaluated under a light microscope (Nikon E200) with oil immersion. When more than 5 mites were detected per square centimeter, the result was recorded as positive.

Ophthalmologic Examination
A complete ophthalmologic examination including visual acuity assessment, standardized slit lamp examination, and fundus examination was done for all patients. Ocular rosacea was diagnosed on detection of 1 or more of the following: watery or bloodshot appearance, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and eyelid margin, eyelid lid and periocular erythema, anterior blepharitis, meibomian gland dysfunction, or irregularity of eyelid margins. All patients were screened for the signs and symptoms of ocular rosacea and underwent other ophthalmologic examinations, including tear function tests. Tear functions were evaluated with Schirmer tests without anesthesia and fluorescein tear breakup time (TBUT). Tear film breakup time was assessed after instillation of 2% fluorescein staining under a cobalt blue filter. The time interval between the last complete blink and the appearance of the first dry spot was recorded. The mean of 3 consecutive measurements was obtained. The Schirmer test was performed without topical anesthesia using a standardized filter strip (Bio-Tech Vision Care). The amount of wetting was measured after 5 minutes. Meibomian gland expressibility was assessed by applying digital pressure to the eyelid margin.

Statistical Analysis
Statistical analysis of the study was performed with SPSS Statistics Version 22.0 (SPSS Inc). Continuous variables were reported as mean (SD), and categorical variables were reported as percentages and counts. Descriptive statistics for numerical variables were created. An independent sample t test was used for normally distributed continuous variables. The Kolmogorov-Smirnov test was used to determine normality. The Schirmer test without anesthesia and TBUT values among groups were compared using one-way analysis of variance. The differences were calculated using the multiple comparison Tukey test. P<.05 was considered statistically significant.

Results

Demographic Characteristics of Rosacea Patients
Sixty eyes of 30 newly diagnosed patients with acne rosacea with Demodex infestation and 60 eyes of 30 newly diagnosed patients with acne rosacea without Demodex infestation were enrolled in this study. The mean age (SD) of the 60 patients was 37.63 (10.01) years. The mean TBUT (SD) of the 120 eyes was 6.65 (3.44) seconds, and the mean Schirmer score (SD) was 12.59 (6.71) mm (Table 1).

Meibomian Gland Dysfunction vs Subgroup of Rosacea Patients
Thirty-four (57%) patients had blepharitis, and 18 (30%) patients had meibomitis. Thirty-five (58.3%) patients had ETR, 5 (8.3%) patients had phymatous rosacea, and 20 (33.4%) patients had PPR (Table 2). Of the Demodex-negative patients, 73.3% (22/30) had ETR, 20% (6/30) had PPR, and 6.7% (2/30) had phymatous rosacea. Of the Demodex-positive patients, 43.3% (13/30) had ETR, 46.7% (14/30) had PPR, and 10% (3/30) had phymatous rosacea (Table 3). Papulopustular rosacea was found to be significantly associated with Demodex positivity (P=.003); neither ETR nor phymatous rosacea was found to be significantly associated with Demodex infestation (P=.66 and P=.13, respectively)(Table 3).

Sixteen (53.3%) patients (32 eyes) in the Demodex-negative group and 21 (70%) patients (42 eyes) in the Demodex-positive group had TBUT values less than 10 seconds. Eighteen (60%) patients (36 eyes) in the Demodex-negative group and 25 (83.3%) patients (50 eyes) in the Demodex-positive group had Schirmer scores less than 10 mm (Table 3). The 2 groups were not significantly different in dry eye findings (P=.25 and P=.29, respectively).

Comment

Inflammation in Rosacea
It is known that the density of nonfloral bacteria as well as D folliculorum and Demodex brevis increases in skin affected by rosacea compared to normal skin. Vascular dilation associated with rosacea that results from sunlight and heat causes increased capillary permeability and creates the ideal environment for the proliferation of D folliculorum. Demodex is thought to act as a vector for the activity of certain other microorganisms, particularly Bacillus oleronius, and thus initiates the inflammatory response associated with rosacea.⁹

One study reported that the inflammation associated with rosacea that was caused by Demodex and other environmental stimuli occurred through toll-like receptor 2 and various cytokines.¹⁰ It has been reported that the abnormal function of toll-like receptor 2 in the epidermis leads to the increased production of cathelicidin. Cathelicidin is an antimicrobial peptide with both vasoactive and proinflammatory activity and has been used as a basis to explain the pathogenesis of facial erythema, flushing, and telangiectasia in the context of rosacea.^11,12 In addition, it has been reported that the increased secretion of proinflammatory cytokines such as IL-1 and gelatinase B in ocular rosacea leads to tearing film abnormalities that result from increased bacterial flora in the eyelids, which subsequently leads to decreased tear drainage and dry eyes.¹³ In addition, B oleronius isolated from a D folliculorum mite from patients with PPR produced proteins that induced an inflammatory immune response in 73% (16/22) of patients with rosacea.¹⁴

Ocular Findings in Rosacea Patients
In our study, PPR was found to be significantly associated with Demodex positivity compared to ETR and phymatous rosacea (P=.003). However, ocular inflammation findings such as blepharitis and meibomitis were not significantly different between Demodex-positive and Demodex-negative patients. Although the mean Schirmer score of Demodex-positive patients was lower than Demodex-negative patients, this difference was not statistically significant. We evaluated a TBUT of less than 10 seconds and a Schirmer score less than 10 mm as dry eye. Accordingly, the number of patients with dry eye was higher in the Demodex-positive group, but this difference was not statistically significant.

Chronic blepharitis, conjunctival inflammation, and meibomian gland dysfunction are among the most common findings of ocular rosacea.^15,16 Patients with ocular rosacea commonly have dry eye and abnormal TBUT and Schirmer scores.¹⁷ In our study, we found that the fluorescein TBUT and Schirmer scores were more likely to be abnormal in the Demodex-positive group, but the difference between the 2 groups was not statistically significant.

It has been reported that proinflammatory cytokines due to a weakened immune system in rosacea patients were increased. The weakened immune system was further supported by the increased concentrations of proinflammatory cytokines such as IL-1 and matrix metalloproteinase 9 in these patients’ tears and the improvement of symptoms after the inhibition of these cytokines.¹¹ Luo et al¹⁸ reported that Demodex inflammation causes dry eye, particularly with D brevis. Ayyildiz and Sezgin¹⁹ reported that Schirmer scores were significantly lower and that the Ocular Surface Disease Index had significantly increased in the Demodex-positive group compared to the Demodex-negative group (P=.001 for both). A Korean study reported that Demodex density was correlated with age, sex, and TBUT results, but there was no significant relationship between Demodex density and Schirmer scores.¹⁶

Sobolewska et al²⁰ administered ivermectin cream 1% to 10 patients with cutaneous and ocular rosacea, but only to the forehead, chin, nose, cheeks, and regions close to the eyelids, and observed a significant improvement in blepharitis (P=.004). They stated that ivermectin, as applied only to the face, suppressed the proinflammatory cytokines associated with rosacea and showed anti-inflammatory effects by reducing Demodex mites.²⁰Li et al²¹ demonstrated a strong correlation between ocular Demodex inflammation and serum reactivity to these bacterial proteins in patients with ocular rosacea, and they found that eyelid margin inflammation and facial rosacea correlated with reactivity to these proteins. These studies suggest a possible role for Demodex infestation and bacterial proteins in the etiology of rosacea.

Gonzalez-Hinojosa et al²² demonstrated that even though eyelash blepharitis was more common in PPR than ETR, there was no statistically significant association between rosacea and Demodex blepharitis. In our study, we found a significant correlation between PPR and Demodex positivity. Also, meibomian gland dysfunction was more common in the Demodex-positive group; however, this result was not statistically significant. One study compared patients with primary demodicosis and patients with rosacea with Demodex-induced blepharitis to healthy controls and found that patients with primary demodicosis and patients with rosacea did not have significantly different ocular findings.²³ In contrast, Forton and De Maertelaer²⁴ reported that patients with PPR had significantly more severe ocular manifestations compared with patients with demodicosis (P=.004).

Mizuno et al²⁵ compared the normal (nonrosacea) population with and without Demodex-infested eyelashes and found that the 2 groups were not significantly different for meibomian gland dysfunction, fluorescein TBUT, or ocular surface discomfort.

Varying results have been reported regarding the association between Demodex and blepharitis or ocular surface discomfort with or without rosacea. In our study, we found that Demodex did not affect tear function tests or meibomian gland function in patients with rosacea. We believe this study is important because it demonstrates the effects of Demodex on ocular findings in patients with cutaneous rosacea.

Limitations
Our study has some limitations. The number of patients was relatively small, resulting in few significant differences between the comparison groups. A larger prospective research study is required to assess the prevalence of Demodex mites in the ocular rosacea population along with associated symptoms and findings.

Conclusion

Rosacea is a chronic disease associated with skin and ocular manifestations that range from mild to severe, that progresses in the form of attacks, and that requires long-term follow-up and treatment. Rosacea most often presents as a disease that causes ocular surface inflammation of varying degrees. Demodex infestation may increase cutaneous or ocular inflammation in rosacea. Therefore, every patient diagnosed with rosacea should be given a dermatologic examination to determine Demodex positivity and an ophthalmologic examination to determine ocular manifestations.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

There is an unmet need to standardize outcomes that are reported in clinical trials of rosacea, according to authors of a new systematic review of rosacea treatment studies.

“Rosacea is a chronic dermatologic condition that affects 16 million Americans,” one of the study authors, Sarah A. Ibrahim, told this news organization after the annual conference of the American Society for Laser Medicine and Surgery. “The features of rosacea, such as inflammatory lesions, redness, burning sensations, and swelling, can have a negative impact on the quality of life for many patients. Additionally, patients with rosacea are at an increased risk for other conditions such as autoimmune diseases, like inflammatory bowel disease.”

In an effort led by principal investigator Murad Alam, MD, vice chair of the department of dermatology at Northwestern University, Chicago, Ms. Ibrahim conducted a systematic review to identify all outcomes that have previously been reported in clinical trials of rosacea, as part of the development of the core outcome set established by the Measurement of Priority Outcome Variables in Dermatologic Surgery (IMPROVED) group. “This has not been done before and is an important first step in understanding what outcomes should be measured in every future clinical study of rosacea,” said Ms. Ibrahim, a medical student at Northwestern University, and predoctoral research fellow in Northwestern’s department of dermatology.

The researchers limited their analysis to randomized, controlled trials of rosacea interventions published between 2010 and 2020 and categorized outcomes into domains based on similar themes.

A total of 58 studies were included in the systematic review, of which 7 (12%) evaluated laser-based interventions. The researchers identified 55 unique outcomes that encompassed eight domains: Quality of life, treatment effects, patient perception of health, clinical assessment, acceptance of care, laboratory assessment, physiological skin assessment, and patient satisfaction. Of the eight domains, clinical assessment-related outcomes were measured in all studies. Nontransient erythema was the most commonly reported outcome (43 studies, 78%), followed by inflammatory lesions (36 studies, 65%) and telangiectasia (22 studies, 40%).

Outcomes pertaining to treatment effects such as adverse events were measured in 49 of the 55 studies (89%), while patient-reported outcomes were measured in 21 (38%). Quality of life and patient satisfaction were reported in 18 (33%) and 13 (24%) studies, respectively.

sruilk/shutterstock

“There were two main take-home messages of our study,” said Ms. Ibrahim, who presented the results at the meeting. “The first is that there is a wide range of outcomes that are reported in clinical trials of rosacea therapies. Second, that there is a need to standardize the outcomes that are reported in clinical trials of rosacea, in order to be able to combine the results from different studies to better understand which interventions for rosacea are most effective.”

She acknowledged certain limitations of the review, including that other trials related to the topic were not included. “Because of the date range and types of studies that we used to narrow down our search, it is possible that additional outcomes were reported in studies that were not included here,” she said.

“This is a very important study because rosacea is a very common condition and one that I have seen more frequently in clinic since the pandemic started,” said Omar Ibrahimi, PhD, MD, a dermatologist with the Connecticut Skin Institute in Stamford, who was asked to comment on the work. “One of the limitations with rosacea studies is that the studies done are often fairly small and the outcome measures are heterogenous. The current study by Ibrahim and coworkers does a wonderful job of highlighting the various outcomes measures used to measure the success of rosacea treatments with energy-based devices.”

This information, he added, “will be very useful for further research studies because it forms the basis for formulating a set of core outcome measures to judge treatment interventions with consensus input from a variety of key opinion leaders. This will prove to be valuable because if we can have a uniform set of outcome measures to judge rosacea treatments with then we will be able to compare the results from different studies better.”

Ms. Ibrahim and colleagues reported having no relevant financial disclosures. Dr. Ibrahimi disclosed that he has been a speaker for both Candela and Cutera and he is currently on the medical advisory board for Cutera.
 

dbrunk@mdedge.com

There is an unmet need to standardize outcomes that are reported in clinical trials of rosacea, according to authors of a new systematic review of rosacea treatment studies.

“Rosacea is a chronic dermatologic condition that affects 16 million Americans,” one of the study authors, Sarah A. Ibrahim, told this news organization after the annual conference of the American Society for Laser Medicine and Surgery. “The features of rosacea, such as inflammatory lesions, redness, burning sensations, and swelling, can have a negative impact on the quality of life for many patients. Additionally, patients with rosacea are at an increased risk for other conditions such as autoimmune diseases, like inflammatory bowel disease.”

In an effort led by principal investigator Murad Alam, MD, vice chair of the department of dermatology at Northwestern University, Chicago, Ms. Ibrahim conducted a systematic review to identify all outcomes that have previously been reported in clinical trials of rosacea, as part of the development of the core outcome set established by the Measurement of Priority Outcome Variables in Dermatologic Surgery (IMPROVED) group. “This has not been done before and is an important first step in understanding what outcomes should be measured in every future clinical study of rosacea,” said Ms. Ibrahim, a medical student at Northwestern University, and predoctoral research fellow in Northwestern’s department of dermatology.

The researchers limited their analysis to randomized, controlled trials of rosacea interventions published between 2010 and 2020 and categorized outcomes into domains based on similar themes.

A total of 58 studies were included in the systematic review, of which 7 (12%) evaluated laser-based interventions. The researchers identified 55 unique outcomes that encompassed eight domains: Quality of life, treatment effects, patient perception of health, clinical assessment, acceptance of care, laboratory assessment, physiological skin assessment, and patient satisfaction. Of the eight domains, clinical assessment-related outcomes were measured in all studies. Nontransient erythema was the most commonly reported outcome (43 studies, 78%), followed by inflammatory lesions (36 studies, 65%) and telangiectasia (22 studies, 40%).

Outcomes pertaining to treatment effects such as adverse events were measured in 49 of the 55 studies (89%), while patient-reported outcomes were measured in 21 (38%). Quality of life and patient satisfaction were reported in 18 (33%) and 13 (24%) studies, respectively.

sruilk/shutterstock

“There were two main take-home messages of our study,” said Ms. Ibrahim, who presented the results at the meeting. “The first is that there is a wide range of outcomes that are reported in clinical trials of rosacea therapies. Second, that there is a need to standardize the outcomes that are reported in clinical trials of rosacea, in order to be able to combine the results from different studies to better understand which interventions for rosacea are most effective.”

She acknowledged certain limitations of the review, including that other trials related to the topic were not included. “Because of the date range and types of studies that we used to narrow down our search, it is possible that additional outcomes were reported in studies that were not included here,” she said.

“This is a very important study because rosacea is a very common condition and one that I have seen more frequently in clinic since the pandemic started,” said Omar Ibrahimi, PhD, MD, a dermatologist with the Connecticut Skin Institute in Stamford, who was asked to comment on the work. “One of the limitations with rosacea studies is that the studies done are often fairly small and the outcome measures are heterogenous. The current study by Ibrahim and coworkers does a wonderful job of highlighting the various outcomes measures used to measure the success of rosacea treatments with energy-based devices.”

This information, he added, “will be very useful for further research studies because it forms the basis for formulating a set of core outcome measures to judge treatment interventions with consensus input from a variety of key opinion leaders. This will prove to be valuable because if we can have a uniform set of outcome measures to judge rosacea treatments with then we will be able to compare the results from different studies better.”

Ms. Ibrahim and colleagues reported having no relevant financial disclosures. Dr. Ibrahimi disclosed that he has been a speaker for both Candela and Cutera and he is currently on the medical advisory board for Cutera.
 

dbrunk@mdedge.com

There is an unmet need to standardize outcomes that are reported in clinical trials of rosacea, according to authors of a new systematic review of rosacea treatment studies.

“Rosacea is a chronic dermatologic condition that affects 16 million Americans,” one of the study authors, Sarah A. Ibrahim, told this news organization after the annual conference of the American Society for Laser Medicine and Surgery. “The features of rosacea, such as inflammatory lesions, redness, burning sensations, and swelling, can have a negative impact on the quality of life for many patients. Additionally, patients with rosacea are at an increased risk for other conditions such as autoimmune diseases, like inflammatory bowel disease.”

In an effort led by principal investigator Murad Alam, MD, vice chair of the department of dermatology at Northwestern University, Chicago, Ms. Ibrahim conducted a systematic review to identify all outcomes that have previously been reported in clinical trials of rosacea, as part of the development of the core outcome set established by the Measurement of Priority Outcome Variables in Dermatologic Surgery (IMPROVED) group. “This has not been done before and is an important first step in understanding what outcomes should be measured in every future clinical study of rosacea,” said Ms. Ibrahim, a medical student at Northwestern University, and predoctoral research fellow in Northwestern’s department of dermatology.

The researchers limited their analysis to randomized, controlled trials of rosacea interventions published between 2010 and 2020 and categorized outcomes into domains based on similar themes.

A total of 58 studies were included in the systematic review, of which 7 (12%) evaluated laser-based interventions. The researchers identified 55 unique outcomes that encompassed eight domains: Quality of life, treatment effects, patient perception of health, clinical assessment, acceptance of care, laboratory assessment, physiological skin assessment, and patient satisfaction. Of the eight domains, clinical assessment-related outcomes were measured in all studies. Nontransient erythema was the most commonly reported outcome (43 studies, 78%), followed by inflammatory lesions (36 studies, 65%) and telangiectasia (22 studies, 40%).

Outcomes pertaining to treatment effects such as adverse events were measured in 49 of the 55 studies (89%), while patient-reported outcomes were measured in 21 (38%). Quality of life and patient satisfaction were reported in 18 (33%) and 13 (24%) studies, respectively.

sruilk/shutterstock

“There were two main take-home messages of our study,” said Ms. Ibrahim, who presented the results at the meeting. “The first is that there is a wide range of outcomes that are reported in clinical trials of rosacea therapies. Second, that there is a need to standardize the outcomes that are reported in clinical trials of rosacea, in order to be able to combine the results from different studies to better understand which interventions for rosacea are most effective.”

She acknowledged certain limitations of the review, including that other trials related to the topic were not included. “Because of the date range and types of studies that we used to narrow down our search, it is possible that additional outcomes were reported in studies that were not included here,” she said.

“This is a very important study because rosacea is a very common condition and one that I have seen more frequently in clinic since the pandemic started,” said Omar Ibrahimi, PhD, MD, a dermatologist with the Connecticut Skin Institute in Stamford, who was asked to comment on the work. “One of the limitations with rosacea studies is that the studies done are often fairly small and the outcome measures are heterogenous. The current study by Ibrahim and coworkers does a wonderful job of highlighting the various outcomes measures used to measure the success of rosacea treatments with energy-based devices.”

This information, he added, “will be very useful for further research studies because it forms the basis for formulating a set of core outcome measures to judge treatment interventions with consensus input from a variety of key opinion leaders. This will prove to be valuable because if we can have a uniform set of outcome measures to judge rosacea treatments with then we will be able to compare the results from different studies better.”

Ms. Ibrahim and colleagues reported having no relevant financial disclosures. Dr. Ibrahimi disclosed that he has been a speaker for both Candela and Cutera and he is currently on the medical advisory board for Cutera.
 

dbrunk@mdedge.com

Oral sarecycline proved rapidly effective for the treatment of moderate to severe papulopustular rosacea in a proof-of-concept pilot study, Linda Stein Gold, MD, said at Innovations in Dermatology: Virtual Spring Conference 2021.

Patrick McNamara Photography

The oral broad-spectrum second-generation tetracyclines doxycycline and minocycline have long been considered first-line therapy for papulopustular rosacea that isn’t cleared using topical agents. But the widespread use of these oral tetracyclines has encouraged the development of antimicrobial resistance. In contrast, sarecycline (Seysara) is a third-generation, narrow-spectrum tetracycline designed to minimize antibiotic resistance. The Food and Drug Administration approved the drug for treatment of moderate to severe acne vulgaris in 2018.

At the meeting, Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit, highlighted a recent pilot study of oral sarecycline for papulopustular rosacea carried out by James Q. Del Rosso, DO, of Las Vegas and coinvestigators. Although she wasn’t involved in the study, she is a veteran clinical trialist with vast experience leading studies of new therapies for rosacea, acne, and other major dermatologic disorders.

The 12-week, prospective, investigator-blinded study included 97 adults with moderate to severe papulopustular rosacea; 72 were randomized to weight-based dosing of once-daily sarecycline, while the 25 controls took a daily oral vitamin.

One coprimary endpoint was achievement of an Investigator Global Assessment score of 0 or 1, meaning clear or almost clear skin, at week 12. The rates were 75% in the sarecycline group and 16% in controls. The other coprimary endpoint was the percent reduction from baseline to week 12 in inflammatory lesion count. Here again, there was a statistically significant difference in favor of the third-generation tetracycline derivative, which achieved an 80% reduction, compared with 50% in the control group.

Of note, the difference was already significant at the first evaluation at week 4, with a 58% reduction in inflammatory lesions in the sarecycline group versus 31% decrease in controls, Dr. Stein Gold observed at the conference, sponsored by MedscapeLIVE! and the producers of the Hawaii Dermatology Seminar and Caribbean Dermatology Symposium.

Also at week 12, 96% of patients on sarecycline reported having no or only trace symptoms of facial burning, 63% had no or only trace facial erythema, and 94% had no or trace facial itch, compared with 76%, 12%, and 76% of controls, respectively. The sarecycline group was also significantly more likely to report no or trace skin dryness and oiliness.

The side-effect profile was favorable and the same as encountered with the use of sarecycline for acne: no major photosensitivity issues, no serious adverse events, and only 2 of the original 75 patients in the active-treatment arm discontinued sarecycline for treatment-emergent headache or gastroenteritis considered “probably” related to the study drug. The investigators deemed further studies of sarecycline for rosacea to be warranted as a potential expanded indication.

Aiming for clear skin rather than ‘almost clear’

Dr. Stein Gold shared her mantra for rosacea therapy: “Always aim for clear skin.”

She cited a study led by Guy Webster, MD, professor of dermatology, Thomas Jefferson University, Philadelphia, in which he and his coinvestigators looked at the durability of treatment response in a pooled analysis of 1,366 rosacea patients in four clinical trials. If patients improved to “almost clear” after treatment, their median time to relapse was 3 months; if they reached “clear,” it was more than 8 months. Also, more clear patients rated their outcomes as excellent and reported that their skin disease no longer had any effect on their quality of life.

“That’s more than a 5-month difference,” Dr. Stein Gold noted. “It shows the importance of really striving to get that skin completely clear.”

The sarecycline study was funded by Almirall, which markets the antibiotic. Dr. Stein Gold, who has no financial relationship with Almirall, has received research funding from and/or served as a consultant to roughly a dozen other pharmaceutical companies. MedscapeLIVE! and this news organization are owned by the same parent company.
 

bjancin@mdedge.com

Oral sarecycline proved rapidly effective for the treatment of moderate to severe papulopustular rosacea in a proof-of-concept pilot study, Linda Stein Gold, MD, said at Innovations in Dermatology: Virtual Spring Conference 2021.

Patrick McNamara Photography

The oral broad-spectrum second-generation tetracyclines doxycycline and minocycline have long been considered first-line therapy for papulopustular rosacea that isn’t cleared using topical agents. But the widespread use of these oral tetracyclines has encouraged the development of antimicrobial resistance. In contrast, sarecycline (Seysara) is a third-generation, narrow-spectrum tetracycline designed to minimize antibiotic resistance. The Food and Drug Administration approved the drug for treatment of moderate to severe acne vulgaris in 2018.

At the meeting, Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit, highlighted a recent pilot study of oral sarecycline for papulopustular rosacea carried out by James Q. Del Rosso, DO, of Las Vegas and coinvestigators. Although she wasn’t involved in the study, she is a veteran clinical trialist with vast experience leading studies of new therapies for rosacea, acne, and other major dermatologic disorders.

The 12-week, prospective, investigator-blinded study included 97 adults with moderate to severe papulopustular rosacea; 72 were randomized to weight-based dosing of once-daily sarecycline, while the 25 controls took a daily oral vitamin.

One coprimary endpoint was achievement of an Investigator Global Assessment score of 0 or 1, meaning clear or almost clear skin, at week 12. The rates were 75% in the sarecycline group and 16% in controls. The other coprimary endpoint was the percent reduction from baseline to week 12 in inflammatory lesion count. Here again, there was a statistically significant difference in favor of the third-generation tetracycline derivative, which achieved an 80% reduction, compared with 50% in the control group.

Of note, the difference was already significant at the first evaluation at week 4, with a 58% reduction in inflammatory lesions in the sarecycline group versus 31% decrease in controls, Dr. Stein Gold observed at the conference, sponsored by MedscapeLIVE! and the producers of the Hawaii Dermatology Seminar and Caribbean Dermatology Symposium.

Also at week 12, 96% of patients on sarecycline reported having no or only trace symptoms of facial burning, 63% had no or only trace facial erythema, and 94% had no or trace facial itch, compared with 76%, 12%, and 76% of controls, respectively. The sarecycline group was also significantly more likely to report no or trace skin dryness and oiliness.

The side-effect profile was favorable and the same as encountered with the use of sarecycline for acne: no major photosensitivity issues, no serious adverse events, and only 2 of the original 75 patients in the active-treatment arm discontinued sarecycline for treatment-emergent headache or gastroenteritis considered “probably” related to the study drug. The investigators deemed further studies of sarecycline for rosacea to be warranted as a potential expanded indication.

Aiming for clear skin rather than ‘almost clear’

Dr. Stein Gold shared her mantra for rosacea therapy: “Always aim for clear skin.”

She cited a study led by Guy Webster, MD, professor of dermatology, Thomas Jefferson University, Philadelphia, in which he and his coinvestigators looked at the durability of treatment response in a pooled analysis of 1,366 rosacea patients in four clinical trials. If patients improved to “almost clear” after treatment, their median time to relapse was 3 months; if they reached “clear,” it was more than 8 months. Also, more clear patients rated their outcomes as excellent and reported that their skin disease no longer had any effect on their quality of life.

“That’s more than a 5-month difference,” Dr. Stein Gold noted. “It shows the importance of really striving to get that skin completely clear.”

The sarecycline study was funded by Almirall, which markets the antibiotic. Dr. Stein Gold, who has no financial relationship with Almirall, has received research funding from and/or served as a consultant to roughly a dozen other pharmaceutical companies. MedscapeLIVE! and this news organization are owned by the same parent company.
 

bjancin@mdedge.com

Oral sarecycline proved rapidly effective for the treatment of moderate to severe papulopustular rosacea in a proof-of-concept pilot study, Linda Stein Gold, MD, said at Innovations in Dermatology: Virtual Spring Conference 2021.

Patrick McNamara Photography

The oral broad-spectrum second-generation tetracyclines doxycycline and minocycline have long been considered first-line therapy for papulopustular rosacea that isn’t cleared using topical agents. But the widespread use of these oral tetracyclines has encouraged the development of antimicrobial resistance. In contrast, sarecycline (Seysara) is a third-generation, narrow-spectrum tetracycline designed to minimize antibiotic resistance. The Food and Drug Administration approved the drug for treatment of moderate to severe acne vulgaris in 2018.

At the meeting, Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit, highlighted a recent pilot study of oral sarecycline for papulopustular rosacea carried out by James Q. Del Rosso, DO, of Las Vegas and coinvestigators. Although she wasn’t involved in the study, she is a veteran clinical trialist with vast experience leading studies of new therapies for rosacea, acne, and other major dermatologic disorders.

The 12-week, prospective, investigator-blinded study included 97 adults with moderate to severe papulopustular rosacea; 72 were randomized to weight-based dosing of once-daily sarecycline, while the 25 controls took a daily oral vitamin.

One coprimary endpoint was achievement of an Investigator Global Assessment score of 0 or 1, meaning clear or almost clear skin, at week 12. The rates were 75% in the sarecycline group and 16% in controls. The other coprimary endpoint was the percent reduction from baseline to week 12 in inflammatory lesion count. Here again, there was a statistically significant difference in favor of the third-generation tetracycline derivative, which achieved an 80% reduction, compared with 50% in the control group.

Of note, the difference was already significant at the first evaluation at week 4, with a 58% reduction in inflammatory lesions in the sarecycline group versus 31% decrease in controls, Dr. Stein Gold observed at the conference, sponsored by MedscapeLIVE! and the producers of the Hawaii Dermatology Seminar and Caribbean Dermatology Symposium.

Also at week 12, 96% of patients on sarecycline reported having no or only trace symptoms of facial burning, 63% had no or only trace facial erythema, and 94% had no or trace facial itch, compared with 76%, 12%, and 76% of controls, respectively. The sarecycline group was also significantly more likely to report no or trace skin dryness and oiliness.

The side-effect profile was favorable and the same as encountered with the use of sarecycline for acne: no major photosensitivity issues, no serious adverse events, and only 2 of the original 75 patients in the active-treatment arm discontinued sarecycline for treatment-emergent headache or gastroenteritis considered “probably” related to the study drug. The investigators deemed further studies of sarecycline for rosacea to be warranted as a potential expanded indication.

Aiming for clear skin rather than ‘almost clear’

Dr. Stein Gold shared her mantra for rosacea therapy: “Always aim for clear skin.”

She cited a study led by Guy Webster, MD, professor of dermatology, Thomas Jefferson University, Philadelphia, in which he and his coinvestigators looked at the durability of treatment response in a pooled analysis of 1,366 rosacea patients in four clinical trials. If patients improved to “almost clear” after treatment, their median time to relapse was 3 months; if they reached “clear,” it was more than 8 months. Also, more clear patients rated their outcomes as excellent and reported that their skin disease no longer had any effect on their quality of life.

“That’s more than a 5-month difference,” Dr. Stein Gold noted. “It shows the importance of really striving to get that skin completely clear.”

The sarecycline study was funded by Almirall, which markets the antibiotic. Dr. Stein Gold, who has no financial relationship with Almirall, has received research funding from and/or served as a consultant to roughly a dozen other pharmaceutical companies. MedscapeLIVE! and this news organization are owned by the same parent company.
 

bjancin@mdedge.com