Atopic Dermatitis

 

Results of a large cohort study in Denmark found that adults with atopic dermatitis (AD) were significantly more likely to be affected by certain ocular conditions, compared with those who did not have AD.

“Keratitis, conjunctivitis, and keratoconus as well as cataracts in patients younger than 50 years occurred more frequently in patients with AD and in a disease severity–dependent manner,” concluded the authors, who wrote that as far as they know, this is the largest study conducted to date of ocular disorders in adults with AD.

The findings, published in June, are based on a population-based sample of 4.25 million adults in Denmark, using national health care and prescription registries, of whom 5,766 had been diagnosed with mild AD and another 4,272 with severe AD. The researchers, led by Jacob Thyssen, MD, PhD, of the department of dermatology and allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, found that 12% of patients with mild AD and 19% of those with severe AD were prescribed at least one anti-inflammatory ocular medication commonly used to treat conjunctivitis or keratitis, compared with only 4.5% of those without AD (J Am Acad Dermatol. 201 Aug;77[2]:280-6).

The investigators also found an elevated risk of a keratitis diagnosis among patients with mild AD (hazard ratio, 1.66; 95% confidence interval, 1.15-2.40) and those with severe AD (HR, 3.17; 95% CI, 2.31-4.35). Severe AD was associated with an elevated risk of keratoconus (HR, 10.01; 95% CI, 5.02-19.96),

Cataracts and glaucoma were not more common among those with AD overall. However, cataracts were increased among those under age 50 years with mild and severe AD, which were significant associations for both, but not among those over age 50 with AD. There were no differences for glaucoma risk associated with AD by age.

The investigators acknowledged that the study could not capture the reasons why anti-inflammatory ocular medicines were prescribed and that such medicines could have been prescribed for conditions other than the ocular conditions.

Capturing the risk of ocular diseases in AD is important, they wrote. They referred to “emerging concern” about the incidence of conjunctivitis with “near-future” biologic treatments for AD and the potential for long-term consequences. They referred to adverse event data from randomized clinical trials of dupilumab, an interleukin-4 receptor–alpha antagonist, approved by the Food and Drug Administration in March 2017 for treatment of moderate to severe AD, which included more cases of conjunctivitis among those treated with the biologic, compared with those on placebo (N Engl J Med. 2016 Dec 15;375:2335-48). A “weak trend” for more cases of conjunctivitis was also reported among treated patients with an IL-13 inhibitor, lebrikizumab, in a phase 2 study of adults with AD, they wrote.

Treatments targeting IL-4 receptor–alpha have been shown to result in increased blood eosinophil counts, and “these elevations might have clinical effects,” Dr. Thyssen and his colleagues wrote, adding: “Notably, eosinophils are pathognomonic for allergic eye disease.”

Dr. Thyssen disclosed funding from the Lundbeck Foundation and honoraria from Roche, Sanofi Genzyme, and LEO Pharma. Three other authors on the study reported research funding and/or honoraria from pharmaceutical firms.

 

 

Results of a large cohort study in Denmark found that adults with atopic dermatitis (AD) were significantly more likely to be affected by certain ocular conditions, compared with those who did not have AD.

“Keratitis, conjunctivitis, and keratoconus as well as cataracts in patients younger than 50 years occurred more frequently in patients with AD and in a disease severity–dependent manner,” concluded the authors, who wrote that as far as they know, this is the largest study conducted to date of ocular disorders in adults with AD.

The findings, published in June, are based on a population-based sample of 4.25 million adults in Denmark, using national health care and prescription registries, of whom 5,766 had been diagnosed with mild AD and another 4,272 with severe AD. The researchers, led by Jacob Thyssen, MD, PhD, of the department of dermatology and allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, found that 12% of patients with mild AD and 19% of those with severe AD were prescribed at least one anti-inflammatory ocular medication commonly used to treat conjunctivitis or keratitis, compared with only 4.5% of those without AD (J Am Acad Dermatol. 201 Aug;77[2]:280-6).

The investigators also found an elevated risk of a keratitis diagnosis among patients with mild AD (hazard ratio, 1.66; 95% confidence interval, 1.15-2.40) and those with severe AD (HR, 3.17; 95% CI, 2.31-4.35). Severe AD was associated with an elevated risk of keratoconus (HR, 10.01; 95% CI, 5.02-19.96),

Cataracts and glaucoma were not more common among those with AD overall. However, cataracts were increased among those under age 50 years with mild and severe AD, which were significant associations for both, but not among those over age 50 with AD. There were no differences for glaucoma risk associated with AD by age.

The investigators acknowledged that the study could not capture the reasons why anti-inflammatory ocular medicines were prescribed and that such medicines could have been prescribed for conditions other than the ocular conditions.

Capturing the risk of ocular diseases in AD is important, they wrote. They referred to “emerging concern” about the incidence of conjunctivitis with “near-future” biologic treatments for AD and the potential for long-term consequences. They referred to adverse event data from randomized clinical trials of dupilumab, an interleukin-4 receptor–alpha antagonist, approved by the Food and Drug Administration in March 2017 for treatment of moderate to severe AD, which included more cases of conjunctivitis among those treated with the biologic, compared with those on placebo (N Engl J Med. 2016 Dec 15;375:2335-48). A “weak trend” for more cases of conjunctivitis was also reported among treated patients with an IL-13 inhibitor, lebrikizumab, in a phase 2 study of adults with AD, they wrote.

Treatments targeting IL-4 receptor–alpha have been shown to result in increased blood eosinophil counts, and “these elevations might have clinical effects,” Dr. Thyssen and his colleagues wrote, adding: “Notably, eosinophils are pathognomonic for allergic eye disease.”

Dr. Thyssen disclosed funding from the Lundbeck Foundation and honoraria from Roche, Sanofi Genzyme, and LEO Pharma. Three other authors on the study reported research funding and/or honoraria from pharmaceutical firms.

 

 

Results of a large cohort study in Denmark found that adults with atopic dermatitis (AD) were significantly more likely to be affected by certain ocular conditions, compared with those who did not have AD.

“Keratitis, conjunctivitis, and keratoconus as well as cataracts in patients younger than 50 years occurred more frequently in patients with AD and in a disease severity–dependent manner,” concluded the authors, who wrote that as far as they know, this is the largest study conducted to date of ocular disorders in adults with AD.

The findings, published in June, are based on a population-based sample of 4.25 million adults in Denmark, using national health care and prescription registries, of whom 5,766 had been diagnosed with mild AD and another 4,272 with severe AD. The researchers, led by Jacob Thyssen, MD, PhD, of the department of dermatology and allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, found that 12% of patients with mild AD and 19% of those with severe AD were prescribed at least one anti-inflammatory ocular medication commonly used to treat conjunctivitis or keratitis, compared with only 4.5% of those without AD (J Am Acad Dermatol. 201 Aug;77[2]:280-6).

The investigators also found an elevated risk of a keratitis diagnosis among patients with mild AD (hazard ratio, 1.66; 95% confidence interval, 1.15-2.40) and those with severe AD (HR, 3.17; 95% CI, 2.31-4.35). Severe AD was associated with an elevated risk of keratoconus (HR, 10.01; 95% CI, 5.02-19.96),

Cataracts and glaucoma were not more common among those with AD overall. However, cataracts were increased among those under age 50 years with mild and severe AD, which were significant associations for both, but not among those over age 50 with AD. There were no differences for glaucoma risk associated with AD by age.

The investigators acknowledged that the study could not capture the reasons why anti-inflammatory ocular medicines were prescribed and that such medicines could have been prescribed for conditions other than the ocular conditions.

Capturing the risk of ocular diseases in AD is important, they wrote. They referred to “emerging concern” about the incidence of conjunctivitis with “near-future” biologic treatments for AD and the potential for long-term consequences. They referred to adverse event data from randomized clinical trials of dupilumab, an interleukin-4 receptor–alpha antagonist, approved by the Food and Drug Administration in March 2017 for treatment of moderate to severe AD, which included more cases of conjunctivitis among those treated with the biologic, compared with those on placebo (N Engl J Med. 2016 Dec 15;375:2335-48). A “weak trend” for more cases of conjunctivitis was also reported among treated patients with an IL-13 inhibitor, lebrikizumab, in a phase 2 study of adults with AD, they wrote.

Treatments targeting IL-4 receptor–alpha have been shown to result in increased blood eosinophil counts, and “these elevations might have clinical effects,” Dr. Thyssen and his colleagues wrote, adding: “Notably, eosinophils are pathognomonic for allergic eye disease.”

Dr. Thyssen disclosed funding from the Lundbeck Foundation and honoraria from Roche, Sanofi Genzyme, and LEO Pharma. Three other authors on the study reported research funding and/or honoraria from pharmaceutical firms.

 

 

CHICAGO – A streamlined set of diagnostic criteria from the American Academy of Dermatology’s most recent consensus criteria for diagnosing atopic dermatitis (AD) produced a specificity of more than 95%, and was also highly sensitive, a prospective analysis found.

“Atopic dermatitis typically presents in childhood and is associated with a worsened quality of life, with severe itch and lack of sleep, and substantial health care costs due to therapeutic management and increased hospitalizations,” study author Jeremy Udkoff said at the World Congress of Pediatric Dermatology. “We also know that in order to treat the disease and to learn more about it, we have to have a good tool for diagnosing it. When it comes to clinical studies and research, we require a systematic and refined set of criteria.”

Mr. Udkoff, a 4th-year medical student at the University of California, San Diego, said that the first AD diagnostic guidelines were published in 1980, the so-called “Hanifin-Rajka criteria” (Acta Derm Venereol Suppl (Stockh). 1980;92:44-7). In order to meet the diagnosis, patients must meet three or more basic features, which include pruritus, typical morphology and distribution, chronic or chronically relapsing dermatitis, and personal or family history of atopy, plus 3 or more of 23 minor criteria such as xerosis, early age of onset, and orbital darkening. “This can be cumbersome and difficult to use in clinical practice and research settings,” Mr. Udkoff said of the criteria. “The sensitivity ranges from 87.9% to 96% and specificity ranges from 77.6% to 93.8%” (Br J Dermatol. 2008;158[4]:754-65).

The next set of commonly used criteria to appear were created by the U.K. working party, for which researchers used logistic regression to systematically create a minimum set of effective criteria for AD (Br J Dermatol. 1994;131[3]:383-96). For these guidelines, meeting a diagnosis of AD requires an itchy skin condition, followed by three or more of the following: a history of flexural involvement; a personal history of asthma or hay fever; a history of general dry skin in the last year; visible flexural eczema, and onset under the age of 2 years. “A subsequent validation trial found [the U.K. working party criteria] to have a low sensitivity, which as you can imagine, could be a very large problem,” he said (Arch Dermatol. 1999;135[5]:514-6).

In 2001, the AAD consensus conference created revised hierarchical criteria known as the AAD consensus criteria (J Am Acad Dermatol. 2003;49[6]:1088-95). “These were initially created for more of a gestalt-type picture of AD in the clinic, but because it flows so well, it’s currently being used in about one-third of clinical trials,” Mr. Udkoff said. “However, [the AAD criteria] have not been validated, so we didn’t know its sensitivity or specificity. In addition, we didn’t have a ‘checkbox’ form that tells us how many of each of the criteria are required to make the diagnosis. We didn’t know how many ‘essential,’ ‘important,’ or ‘associated’ features we need to make this diagnosis.”

For the current study, he and his associates set out to determine how many “essential,” “important,” and “associated” criteria are necessary to make the AAD consensus criteria work. They also set out to create a usable checkbox form, validate the criteria, and compare it to the Hanifin-Rajka (HR) and U.K. criteria. To accomplish this, they created a questionnaire comprised of HR, U.K., and AAD criteria, examined the criteria on 60 subjects with and without AD, and compared the diagnostic features of each of those criteria against a gold standard dermatology diagnosis from one of seven pediatric dermatologists. Next, they ranked all 56 possible AAD criterion combinations based on their overall sensitivity and specificity, and chose the most predictive combination. “Once we had the optimal set of criteria, we validated it on a new cohort to determine its sensitivity and specificity, and compared it with the classic HR and U.K. criteria,” Mr. Udkoff explained.

Overall, the researchers evaluated findings from 100 subjects: 58 with AD, and 42 controls. Those with AD were about 3 years younger, compared with controls (a mean age of 5 years vs. about 8 years, respectively). About 40% of patients were Hispanic and about 30% were white. Mr. Udkoff and his associates confirmed the hierarchical structure of the AAD criteria and found that individual “essential” AAD criteria of pruritus, typical AD pattern, and chronic/relapsing course each had a sensitivity that exceeded 96%. This was followed by the “important” criteria of early age of onset, atopy, and xerosis, which had a sensitivity that ranged between 88% and 95%, while the associated criteria had a sensitivity that ranged between 50% and 85%.

Next, the researchers systematically tested all combinations of the AAD criteria and found that three “essential” AAD criteria, two or more of the “important” criteria, and one or more of the “associated” criteria were optimal in diagnosing AD. Mr. Udkoff noted that the findings can be translated into a simple “3-2-1 rule” that “is both practical and pragmatic,” he said. Using this rule, sensitivity was 91.4% and specificity was 95.2%.

Currently, the researchers are working to validate this criteria in different subgroups of patients. To date, they have found that children younger than 1.5 years get one bonus “essential” criteria for being an infant, so for that population a 2-2-1 rule would apply.

Mr. Udkoff reported that the research was supported by a training grant from the National Institutes of Health. He reported having no financial disclosures.

 

dbrunk@frontlinemedcom.com

 

CHICAGO – A streamlined set of diagnostic criteria from the American Academy of Dermatology’s most recent consensus criteria for diagnosing atopic dermatitis (AD) produced a specificity of more than 95%, and was also highly sensitive, a prospective analysis found.

“Atopic dermatitis typically presents in childhood and is associated with a worsened quality of life, with severe itch and lack of sleep, and substantial health care costs due to therapeutic management and increased hospitalizations,” study author Jeremy Udkoff said at the World Congress of Pediatric Dermatology. “We also know that in order to treat the disease and to learn more about it, we have to have a good tool for diagnosing it. When it comes to clinical studies and research, we require a systematic and refined set of criteria.”

Mr. Udkoff, a 4th-year medical student at the University of California, San Diego, said that the first AD diagnostic guidelines were published in 1980, the so-called “Hanifin-Rajka criteria” (Acta Derm Venereol Suppl (Stockh). 1980;92:44-7). In order to meet the diagnosis, patients must meet three or more basic features, which include pruritus, typical morphology and distribution, chronic or chronically relapsing dermatitis, and personal or family history of atopy, plus 3 or more of 23 minor criteria such as xerosis, early age of onset, and orbital darkening. “This can be cumbersome and difficult to use in clinical practice and research settings,” Mr. Udkoff said of the criteria. “The sensitivity ranges from 87.9% to 96% and specificity ranges from 77.6% to 93.8%” (Br J Dermatol. 2008;158[4]:754-65).

The next set of commonly used criteria to appear were created by the U.K. working party, for which researchers used logistic regression to systematically create a minimum set of effective criteria for AD (Br J Dermatol. 1994;131[3]:383-96). For these guidelines, meeting a diagnosis of AD requires an itchy skin condition, followed by three or more of the following: a history of flexural involvement; a personal history of asthma or hay fever; a history of general dry skin in the last year; visible flexural eczema, and onset under the age of 2 years. “A subsequent validation trial found [the U.K. working party criteria] to have a low sensitivity, which as you can imagine, could be a very large problem,” he said (Arch Dermatol. 1999;135[5]:514-6).

In 2001, the AAD consensus conference created revised hierarchical criteria known as the AAD consensus criteria (J Am Acad Dermatol. 2003;49[6]:1088-95). “These were initially created for more of a gestalt-type picture of AD in the clinic, but because it flows so well, it’s currently being used in about one-third of clinical trials,” Mr. Udkoff said. “However, [the AAD criteria] have not been validated, so we didn’t know its sensitivity or specificity. In addition, we didn’t have a ‘checkbox’ form that tells us how many of each of the criteria are required to make the diagnosis. We didn’t know how many ‘essential,’ ‘important,’ or ‘associated’ features we need to make this diagnosis.”

For the current study, he and his associates set out to determine how many “essential,” “important,” and “associated” criteria are necessary to make the AAD consensus criteria work. They also set out to create a usable checkbox form, validate the criteria, and compare it to the Hanifin-Rajka (HR) and U.K. criteria. To accomplish this, they created a questionnaire comprised of HR, U.K., and AAD criteria, examined the criteria on 60 subjects with and without AD, and compared the diagnostic features of each of those criteria against a gold standard dermatology diagnosis from one of seven pediatric dermatologists. Next, they ranked all 56 possible AAD criterion combinations based on their overall sensitivity and specificity, and chose the most predictive combination. “Once we had the optimal set of criteria, we validated it on a new cohort to determine its sensitivity and specificity, and compared it with the classic HR and U.K. criteria,” Mr. Udkoff explained.

Overall, the researchers evaluated findings from 100 subjects: 58 with AD, and 42 controls. Those with AD were about 3 years younger, compared with controls (a mean age of 5 years vs. about 8 years, respectively). About 40% of patients were Hispanic and about 30% were white. Mr. Udkoff and his associates confirmed the hierarchical structure of the AAD criteria and found that individual “essential” AAD criteria of pruritus, typical AD pattern, and chronic/relapsing course each had a sensitivity that exceeded 96%. This was followed by the “important” criteria of early age of onset, atopy, and xerosis, which had a sensitivity that ranged between 88% and 95%, while the associated criteria had a sensitivity that ranged between 50% and 85%.

Next, the researchers systematically tested all combinations of the AAD criteria and found that three “essential” AAD criteria, two or more of the “important” criteria, and one or more of the “associated” criteria were optimal in diagnosing AD. Mr. Udkoff noted that the findings can be translated into a simple “3-2-1 rule” that “is both practical and pragmatic,” he said. Using this rule, sensitivity was 91.4% and specificity was 95.2%.

Currently, the researchers are working to validate this criteria in different subgroups of patients. To date, they have found that children younger than 1.5 years get one bonus “essential” criteria for being an infant, so for that population a 2-2-1 rule would apply.

Mr. Udkoff reported that the research was supported by a training grant from the National Institutes of Health. He reported having no financial disclosures.

 

dbrunk@frontlinemedcom.com

 

CHICAGO – A streamlined set of diagnostic criteria from the American Academy of Dermatology’s most recent consensus criteria for diagnosing atopic dermatitis (AD) produced a specificity of more than 95%, and was also highly sensitive, a prospective analysis found.

“Atopic dermatitis typically presents in childhood and is associated with a worsened quality of life, with severe itch and lack of sleep, and substantial health care costs due to therapeutic management and increased hospitalizations,” study author Jeremy Udkoff said at the World Congress of Pediatric Dermatology. “We also know that in order to treat the disease and to learn more about it, we have to have a good tool for diagnosing it. When it comes to clinical studies and research, we require a systematic and refined set of criteria.”

Mr. Udkoff, a 4th-year medical student at the University of California, San Diego, said that the first AD diagnostic guidelines were published in 1980, the so-called “Hanifin-Rajka criteria” (Acta Derm Venereol Suppl (Stockh). 1980;92:44-7). In order to meet the diagnosis, patients must meet three or more basic features, which include pruritus, typical morphology and distribution, chronic or chronically relapsing dermatitis, and personal or family history of atopy, plus 3 or more of 23 minor criteria such as xerosis, early age of onset, and orbital darkening. “This can be cumbersome and difficult to use in clinical practice and research settings,” Mr. Udkoff said of the criteria. “The sensitivity ranges from 87.9% to 96% and specificity ranges from 77.6% to 93.8%” (Br J Dermatol. 2008;158[4]:754-65).

The next set of commonly used criteria to appear were created by the U.K. working party, for which researchers used logistic regression to systematically create a minimum set of effective criteria for AD (Br J Dermatol. 1994;131[3]:383-96). For these guidelines, meeting a diagnosis of AD requires an itchy skin condition, followed by three or more of the following: a history of flexural involvement; a personal history of asthma or hay fever; a history of general dry skin in the last year; visible flexural eczema, and onset under the age of 2 years. “A subsequent validation trial found [the U.K. working party criteria] to have a low sensitivity, which as you can imagine, could be a very large problem,” he said (Arch Dermatol. 1999;135[5]:514-6).

In 2001, the AAD consensus conference created revised hierarchical criteria known as the AAD consensus criteria (J Am Acad Dermatol. 2003;49[6]:1088-95). “These were initially created for more of a gestalt-type picture of AD in the clinic, but because it flows so well, it’s currently being used in about one-third of clinical trials,” Mr. Udkoff said. “However, [the AAD criteria] have not been validated, so we didn’t know its sensitivity or specificity. In addition, we didn’t have a ‘checkbox’ form that tells us how many of each of the criteria are required to make the diagnosis. We didn’t know how many ‘essential,’ ‘important,’ or ‘associated’ features we need to make this diagnosis.”

For the current study, he and his associates set out to determine how many “essential,” “important,” and “associated” criteria are necessary to make the AAD consensus criteria work. They also set out to create a usable checkbox form, validate the criteria, and compare it to the Hanifin-Rajka (HR) and U.K. criteria. To accomplish this, they created a questionnaire comprised of HR, U.K., and AAD criteria, examined the criteria on 60 subjects with and without AD, and compared the diagnostic features of each of those criteria against a gold standard dermatology diagnosis from one of seven pediatric dermatologists. Next, they ranked all 56 possible AAD criterion combinations based on their overall sensitivity and specificity, and chose the most predictive combination. “Once we had the optimal set of criteria, we validated it on a new cohort to determine its sensitivity and specificity, and compared it with the classic HR and U.K. criteria,” Mr. Udkoff explained.

Overall, the researchers evaluated findings from 100 subjects: 58 with AD, and 42 controls. Those with AD were about 3 years younger, compared with controls (a mean age of 5 years vs. about 8 years, respectively). About 40% of patients were Hispanic and about 30% were white. Mr. Udkoff and his associates confirmed the hierarchical structure of the AAD criteria and found that individual “essential” AAD criteria of pruritus, typical AD pattern, and chronic/relapsing course each had a sensitivity that exceeded 96%. This was followed by the “important” criteria of early age of onset, atopy, and xerosis, which had a sensitivity that ranged between 88% and 95%, while the associated criteria had a sensitivity that ranged between 50% and 85%.

Next, the researchers systematically tested all combinations of the AAD criteria and found that three “essential” AAD criteria, two or more of the “important” criteria, and one or more of the “associated” criteria were optimal in diagnosing AD. Mr. Udkoff noted that the findings can be translated into a simple “3-2-1 rule” that “is both practical and pragmatic,” he said. Using this rule, sensitivity was 91.4% and specificity was 95.2%.

Currently, the researchers are working to validate this criteria in different subgroups of patients. To date, they have found that children younger than 1.5 years get one bonus “essential” criteria for being an infant, so for that population a 2-2-1 rule would apply.

Mr. Udkoff reported that the research was supported by a training grant from the National Institutes of Health. He reported having no financial disclosures.

 

dbrunk@frontlinemedcom.com

 

CHICAGO – Sometimes, the skin can provide the first clues that a patient has been exposed to a drug product that has been adulterated or an over-the-counter product illegally sold in this country that contains a prescription medication, according to pediatric dermatologist Scott Norton, MD.

Speaking at the World Congress of Pediatric Dermatology, he reviewed some of the reactions associated with exposure to counterfeit drugs, contraband drugs, as well as products, misrepresented as drugs that do not include any active pharmaceutical ingredients. The worldwide market for these products is a “hugely profitable industry,” and the scope of the problem should not be underestimated, said Dr. Norton, chief of dermatology at Children’s National Health System, Washington.

Children's Hospital

Examples include completely fraudulent formulations, from fake vaccines being distributed in China and Nigeria and counterfeit antimalarials in Cambodia to “contraceptive” pills in Brazil that contain no contraceptive ingredients. In addition, many Asian so-called herbal remedies are actually adulterated with corticosteroids, antibiotics, and other prescription medications. Another issue, he noted, is that substandard medications might contain too much or too little of the active ingredient listed on the label, including adulterated vehicles or fillers. In other cases, they may be contaminated, as happened with the CNS-injectable steroids that caused serious fungal infections and deaths in the United States.

It’s particularly important to have a high index of suspicion for such products given an increasingly mobile worldwide population. Today, patients and their family members who travel out of the country – and even local shopkeepers – may bring in these sorts of products from outside the United States, many of which would require a prescription in the United States.

In the United States, there have been several reports of a mysterious fixed drug eruption in patients reported to have taken Baczol, a cold and flu remedy available over the counter in El Salvador for upper respiratory infections. Two of the ingredients listed on the Baczol label are sulfamethoxazole and trimethoprim, two prescription antibiotics. After determining that two Salvadoran American children with a suspected fixed drug eruption had taken a Baczol product, Dr. Norton, with the aid of medical students, was able to find Baczol containing trimethoprim-sulfamethoxazole for sale over the counter in more than one-third of the shops visited in the greater Washington area (MMWR Morb Mortal Wkly Rep. 2013 Nov 22;62[46]:914-6). Eventually, the Food and Drug Administration issued a consumer alert regarding certain Baczol products containing these ingredients, but Dr. Norton said he is still concerned about the possibility for more grave hypersensitivity reactions to these sulfa antibiotics in the Salvadoran product.

CDC, MMWR https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6246a2.htm#fig

In the United States, children treated with adulterated preparations for atopic dermatitis may present with striae and other dermatologic stigmata of potent topical steroid use in areas of atopy; for example, one such preparation was found to contain clobetasol. In a commentary recently published online in JAMA Dermatology, Hongfu Xie, MD, and two other Chinese dermatologists described the pervasive presence of topical steroids in Chinese cosmetic preparations (JAMA Dermatol. 2017 Jul 5. doi: 10.1001/jamadermatol.2017.1615).

Sometimes, said Dr. Norton, the problem lies in the lack of an expected ingredient. He and his team at Children’s National Health System helped solve a medical mystery involving a skin ailment in very premature infants with cholestasis. An interdisciplinary team was convened after the neonatal intensive care unit at the hospital saw its third infant with severe blistering and erosions in an acral, perianal, and perioral pattern that did not respond to empiric treatment for herpes simplex virus and staphylococcal infection – a pattern reminiscent of zinc deficiency dermatitis. Dietitians reported that there was a nationwide shortage of sterile injectable zinc, so total parenteral nutrition was being formulated without zinc. All three of the premature infants were receiving total parenteral nutrition and were so premature that they had insufficient zinc stores. The problem was identified and corrected (MMWR 2014 Jan. 17;63[02];35-7).

A more pervasive issue, which has global significance, pertains to counterfeit vaccines prepared with absolutely no vaccine components, often made in China or Nigeria with high-quality and sophisticated packaging, said Dr. Norton.

Keeping a lid on counterfeit drugs is challenging since there are so many potential entry points into the supply chain, Dr. Norton pointed out. Weak points include mislabeled raw ingredients, packaging, storage, transportation, repackaging, and distribution. The proliferation of online pharmacies also makes regulation more difficult.

There is some international cooperation to detect and combat drug counterfeiting and adulteration: For example, Interpol, the International Coalition of Medicines Regulatory Authorities, the Pharmaceutical Security Institute, and even the United Nations are developing cooperative strategies to combat the problem.

In the meantime, he emphasized that physicians must maintain a high index of suspicion and keep in mind that the first signs of adulterated drugs or prescription drugs available OTC may appear on the skin.

Dr. Norton reported no conflicts of interest.

 

koakes@frontlinemedcom.com

On Twitter @karioakes

 

CHICAGO – Sometimes, the skin can provide the first clues that a patient has been exposed to a drug product that has been adulterated or an over-the-counter product illegally sold in this country that contains a prescription medication, according to pediatric dermatologist Scott Norton, MD.

Speaking at the World Congress of Pediatric Dermatology, he reviewed some of the reactions associated with exposure to counterfeit drugs, contraband drugs, as well as products, misrepresented as drugs that do not include any active pharmaceutical ingredients. The worldwide market for these products is a “hugely profitable industry,” and the scope of the problem should not be underestimated, said Dr. Norton, chief of dermatology at Children’s National Health System, Washington.

Children's Hospital

Examples include completely fraudulent formulations, from fake vaccines being distributed in China and Nigeria and counterfeit antimalarials in Cambodia to “contraceptive” pills in Brazil that contain no contraceptive ingredients. In addition, many Asian so-called herbal remedies are actually adulterated with corticosteroids, antibiotics, and other prescription medications. Another issue, he noted, is that substandard medications might contain too much or too little of the active ingredient listed on the label, including adulterated vehicles or fillers. In other cases, they may be contaminated, as happened with the CNS-injectable steroids that caused serious fungal infections and deaths in the United States.

It’s particularly important to have a high index of suspicion for such products given an increasingly mobile worldwide population. Today, patients and their family members who travel out of the country – and even local shopkeepers – may bring in these sorts of products from outside the United States, many of which would require a prescription in the United States.

In the United States, there have been several reports of a mysterious fixed drug eruption in patients reported to have taken Baczol, a cold and flu remedy available over the counter in El Salvador for upper respiratory infections. Two of the ingredients listed on the Baczol label are sulfamethoxazole and trimethoprim, two prescription antibiotics. After determining that two Salvadoran American children with a suspected fixed drug eruption had taken a Baczol product, Dr. Norton, with the aid of medical students, was able to find Baczol containing trimethoprim-sulfamethoxazole for sale over the counter in more than one-third of the shops visited in the greater Washington area (MMWR Morb Mortal Wkly Rep. 2013 Nov 22;62[46]:914-6). Eventually, the Food and Drug Administration issued a consumer alert regarding certain Baczol products containing these ingredients, but Dr. Norton said he is still concerned about the possibility for more grave hypersensitivity reactions to these sulfa antibiotics in the Salvadoran product.

CDC, MMWR https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6246a2.htm#fig

In the United States, children treated with adulterated preparations for atopic dermatitis may present with striae and other dermatologic stigmata of potent topical steroid use in areas of atopy; for example, one such preparation was found to contain clobetasol. In a commentary recently published online in JAMA Dermatology, Hongfu Xie, MD, and two other Chinese dermatologists described the pervasive presence of topical steroids in Chinese cosmetic preparations (JAMA Dermatol. 2017 Jul 5. doi: 10.1001/jamadermatol.2017.1615).

Sometimes, said Dr. Norton, the problem lies in the lack of an expected ingredient. He and his team at Children’s National Health System helped solve a medical mystery involving a skin ailment in very premature infants with cholestasis. An interdisciplinary team was convened after the neonatal intensive care unit at the hospital saw its third infant with severe blistering and erosions in an acral, perianal, and perioral pattern that did not respond to empiric treatment for herpes simplex virus and staphylococcal infection – a pattern reminiscent of zinc deficiency dermatitis. Dietitians reported that there was a nationwide shortage of sterile injectable zinc, so total parenteral nutrition was being formulated without zinc. All three of the premature infants were receiving total parenteral nutrition and were so premature that they had insufficient zinc stores. The problem was identified and corrected (MMWR 2014 Jan. 17;63[02];35-7).

A more pervasive issue, which has global significance, pertains to counterfeit vaccines prepared with absolutely no vaccine components, often made in China or Nigeria with high-quality and sophisticated packaging, said Dr. Norton.

Keeping a lid on counterfeit drugs is challenging since there are so many potential entry points into the supply chain, Dr. Norton pointed out. Weak points include mislabeled raw ingredients, packaging, storage, transportation, repackaging, and distribution. The proliferation of online pharmacies also makes regulation more difficult.

There is some international cooperation to detect and combat drug counterfeiting and adulteration: For example, Interpol, the International Coalition of Medicines Regulatory Authorities, the Pharmaceutical Security Institute, and even the United Nations are developing cooperative strategies to combat the problem.

In the meantime, he emphasized that physicians must maintain a high index of suspicion and keep in mind that the first signs of adulterated drugs or prescription drugs available OTC may appear on the skin.

Dr. Norton reported no conflicts of interest.

 

koakes@frontlinemedcom.com

On Twitter @karioakes

 

CHICAGO – Sometimes, the skin can provide the first clues that a patient has been exposed to a drug product that has been adulterated or an over-the-counter product illegally sold in this country that contains a prescription medication, according to pediatric dermatologist Scott Norton, MD.

Speaking at the World Congress of Pediatric Dermatology, he reviewed some of the reactions associated with exposure to counterfeit drugs, contraband drugs, as well as products, misrepresented as drugs that do not include any active pharmaceutical ingredients. The worldwide market for these products is a “hugely profitable industry,” and the scope of the problem should not be underestimated, said Dr. Norton, chief of dermatology at Children’s National Health System, Washington.

Children's Hospital

Examples include completely fraudulent formulations, from fake vaccines being distributed in China and Nigeria and counterfeit antimalarials in Cambodia to “contraceptive” pills in Brazil that contain no contraceptive ingredients. In addition, many Asian so-called herbal remedies are actually adulterated with corticosteroids, antibiotics, and other prescription medications. Another issue, he noted, is that substandard medications might contain too much or too little of the active ingredient listed on the label, including adulterated vehicles or fillers. In other cases, they may be contaminated, as happened with the CNS-injectable steroids that caused serious fungal infections and deaths in the United States.

It’s particularly important to have a high index of suspicion for such products given an increasingly mobile worldwide population. Today, patients and their family members who travel out of the country – and even local shopkeepers – may bring in these sorts of products from outside the United States, many of which would require a prescription in the United States.

In the United States, there have been several reports of a mysterious fixed drug eruption in patients reported to have taken Baczol, a cold and flu remedy available over the counter in El Salvador for upper respiratory infections. Two of the ingredients listed on the Baczol label are sulfamethoxazole and trimethoprim, two prescription antibiotics. After determining that two Salvadoran American children with a suspected fixed drug eruption had taken a Baczol product, Dr. Norton, with the aid of medical students, was able to find Baczol containing trimethoprim-sulfamethoxazole for sale over the counter in more than one-third of the shops visited in the greater Washington area (MMWR Morb Mortal Wkly Rep. 2013 Nov 22;62[46]:914-6). Eventually, the Food and Drug Administration issued a consumer alert regarding certain Baczol products containing these ingredients, but Dr. Norton said he is still concerned about the possibility for more grave hypersensitivity reactions to these sulfa antibiotics in the Salvadoran product.

CDC, MMWR https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6246a2.htm#fig

In the United States, children treated with adulterated preparations for atopic dermatitis may present with striae and other dermatologic stigmata of potent topical steroid use in areas of atopy; for example, one such preparation was found to contain clobetasol. In a commentary recently published online in JAMA Dermatology, Hongfu Xie, MD, and two other Chinese dermatologists described the pervasive presence of topical steroids in Chinese cosmetic preparations (JAMA Dermatol. 2017 Jul 5. doi: 10.1001/jamadermatol.2017.1615).

Sometimes, said Dr. Norton, the problem lies in the lack of an expected ingredient. He and his team at Children’s National Health System helped solve a medical mystery involving a skin ailment in very premature infants with cholestasis. An interdisciplinary team was convened after the neonatal intensive care unit at the hospital saw its third infant with severe blistering and erosions in an acral, perianal, and perioral pattern that did not respond to empiric treatment for herpes simplex virus and staphylococcal infection – a pattern reminiscent of zinc deficiency dermatitis. Dietitians reported that there was a nationwide shortage of sterile injectable zinc, so total parenteral nutrition was being formulated without zinc. All three of the premature infants were receiving total parenteral nutrition and were so premature that they had insufficient zinc stores. The problem was identified and corrected (MMWR 2014 Jan. 17;63[02];35-7).

A more pervasive issue, which has global significance, pertains to counterfeit vaccines prepared with absolutely no vaccine components, often made in China or Nigeria with high-quality and sophisticated packaging, said Dr. Norton.

Keeping a lid on counterfeit drugs is challenging since there are so many potential entry points into the supply chain, Dr. Norton pointed out. Weak points include mislabeled raw ingredients, packaging, storage, transportation, repackaging, and distribution. The proliferation of online pharmacies also makes regulation more difficult.

There is some international cooperation to detect and combat drug counterfeiting and adulteration: For example, Interpol, the International Coalition of Medicines Regulatory Authorities, the Pharmaceutical Security Institute, and even the United Nations are developing cooperative strategies to combat the problem.

In the meantime, he emphasized that physicians must maintain a high index of suspicion and keep in mind that the first signs of adulterated drugs or prescription drugs available OTC may appear on the skin.

Dr. Norton reported no conflicts of interest.

 

koakes@frontlinemedcom.com

On Twitter @karioakes

 

CHICAGO – There is considerable variability and poor documentation of severity assessments used for inclusion criteria and baseline severity evaluations in randomized, controlled pediatric atopic dermatitis (AD) trials, results from a systematic review showed.

“It is important for clinicians and investigators to recognize that these differences may limit our ability to reproduce trials, interpret individual studies, and compare results between studies of similar target populations for severity,” lead study author Rishi Chopra, MS, said in an interview in advance of the World Congress of Pediatric Dermatology. “Moreover, this heterogeneity should be considered when retroactively pooling results for meta-analyses of pediatric atopic dermatitis randomized, controlled trials.”

According to Mr. Chopra, a fourth-year medical student at the State University of New York at Stony Brook and visiting predoctoral research fellow in the department of dermatology at Northwestern University, Chicago, clinician assessments of AD may be subjective, inaccurate, and difficult to standardize. Consequently, objective severity scoring assessments were developed to accurately quantitate and communicate disease burden. “However, there are now more than 60 of these unique severity assessments, fewer than 20 have undergone preliminary validation, and only 3 are sufficiently validated and recommended for use,” he said. “This represents a huge challenge for clinical trials as the combination of inadequately validated assessments and heterogeneity in assessment used in clinical trials may prevent both the accurate interpretation of results within an individual trial and comparison of interventions amongst trials.”

In an effort to evaluate the documentation and characterize the severity assessments used in inclusion criteria and baseline evaluations for randomized, controlled trials of pediatric AD internationally, the researchers performed a systematic review of relevant studies contained in the Cochrane Library, Embase, LILACS, GREAT, MEDLINE, and Scopus databases during 2007-2016. Inclusion criteria were RCT with a pharmacological intervention and any comparison with a control group, children, and males or females. In all, 89 studies met the inclusion/exclusion criteria. Most (70.8%) were studies of pediatric populations aged 0-17 years, and almost 17% were studies of infants aged 0-1 years. The most common target populations were mild-moderate AD (31.5%), moderate-severe AD (18.0%), or undefined (36.0%).

Mr. Chopra and his associates found that the most commonly used severity indices were Scoring AD (SCORAD) in 29.2%, Body Surface Area (BSA) in 16.9%, and global assessments in 13.4%, while the most common assessments of baseline severity were SCORAD in 43.8%, global assessments in 20.2%, Eczema Area and Severity Index in 17.9%, BSA in 14.6%, and visual itch in 13.5%. Only 85.4% of studies recorded the severity assessments used for recruiting the predefined target population and only 76.4% of studies documented baseline severity.

There was considerable heterogeneity across studies, as 16 unique assessments were used as inclusion criteria and 34 assessments were used to evaluate baseline severity. “In addition, even within an individual study, there was substantial discordance in their use as only 71.2% of studies used the same assessments for inclusion and documenting baseline disease severity,” Mr. Chopra said. “Altogether, this multidimensional lack of documentation and heterogeneity of inclusion criteria and baseline severity assessments limits our ability to assess whether the recruitment methods for patients were adequate and confirm whether the intended target population for severity was successfully enrolled.”

He acknowledged certain limitations of the study, including the fact that it may not be generalizable to nonpharmacological interventional trials or noninterventional studies. “In addition, we could only conduct an analysis for studies that provided adequate documentation of inclusion criteria and baseline severity,” Mr. Chopra said. “Thus, those studies that did not provide this information were left out. Nevertheless, across all studies, the uniformity and concordance between assessments likely are even more negatively impacted. It should also be noted that lack of documentation of assessments for inclusion criteria and baseline severity does not imply lack of their utilization. Finally, it is important to acknowledge that AD’s diverse phenotype and relapsing and remitting course may result in the unavoidable heterogeneity of severity assessment use. This may actually help to capture a broader range of disease and improve the external validity of results.”

He reported having no financial disclosures.
 

dbrunk@frontlinemedcom.com

 

CHICAGO – There is considerable variability and poor documentation of severity assessments used for inclusion criteria and baseline severity evaluations in randomized, controlled pediatric atopic dermatitis (AD) trials, results from a systematic review showed.

“It is important for clinicians and investigators to recognize that these differences may limit our ability to reproduce trials, interpret individual studies, and compare results between studies of similar target populations for severity,” lead study author Rishi Chopra, MS, said in an interview in advance of the World Congress of Pediatric Dermatology. “Moreover, this heterogeneity should be considered when retroactively pooling results for meta-analyses of pediatric atopic dermatitis randomized, controlled trials.”

According to Mr. Chopra, a fourth-year medical student at the State University of New York at Stony Brook and visiting predoctoral research fellow in the department of dermatology at Northwestern University, Chicago, clinician assessments of AD may be subjective, inaccurate, and difficult to standardize. Consequently, objective severity scoring assessments were developed to accurately quantitate and communicate disease burden. “However, there are now more than 60 of these unique severity assessments, fewer than 20 have undergone preliminary validation, and only 3 are sufficiently validated and recommended for use,” he said. “This represents a huge challenge for clinical trials as the combination of inadequately validated assessments and heterogeneity in assessment used in clinical trials may prevent both the accurate interpretation of results within an individual trial and comparison of interventions amongst trials.”

In an effort to evaluate the documentation and characterize the severity assessments used in inclusion criteria and baseline evaluations for randomized, controlled trials of pediatric AD internationally, the researchers performed a systematic review of relevant studies contained in the Cochrane Library, Embase, LILACS, GREAT, MEDLINE, and Scopus databases during 2007-2016. Inclusion criteria were RCT with a pharmacological intervention and any comparison with a control group, children, and males or females. In all, 89 studies met the inclusion/exclusion criteria. Most (70.8%) were studies of pediatric populations aged 0-17 years, and almost 17% were studies of infants aged 0-1 years. The most common target populations were mild-moderate AD (31.5%), moderate-severe AD (18.0%), or undefined (36.0%).

Mr. Chopra and his associates found that the most commonly used severity indices were Scoring AD (SCORAD) in 29.2%, Body Surface Area (BSA) in 16.9%, and global assessments in 13.4%, while the most common assessments of baseline severity were SCORAD in 43.8%, global assessments in 20.2%, Eczema Area and Severity Index in 17.9%, BSA in 14.6%, and visual itch in 13.5%. Only 85.4% of studies recorded the severity assessments used for recruiting the predefined target population and only 76.4% of studies documented baseline severity.

There was considerable heterogeneity across studies, as 16 unique assessments were used as inclusion criteria and 34 assessments were used to evaluate baseline severity. “In addition, even within an individual study, there was substantial discordance in their use as only 71.2% of studies used the same assessments for inclusion and documenting baseline disease severity,” Mr. Chopra said. “Altogether, this multidimensional lack of documentation and heterogeneity of inclusion criteria and baseline severity assessments limits our ability to assess whether the recruitment methods for patients were adequate and confirm whether the intended target population for severity was successfully enrolled.”

He acknowledged certain limitations of the study, including the fact that it may not be generalizable to nonpharmacological interventional trials or noninterventional studies. “In addition, we could only conduct an analysis for studies that provided adequate documentation of inclusion criteria and baseline severity,” Mr. Chopra said. “Thus, those studies that did not provide this information were left out. Nevertheless, across all studies, the uniformity and concordance between assessments likely are even more negatively impacted. It should also be noted that lack of documentation of assessments for inclusion criteria and baseline severity does not imply lack of their utilization. Finally, it is important to acknowledge that AD’s diverse phenotype and relapsing and remitting course may result in the unavoidable heterogeneity of severity assessment use. This may actually help to capture a broader range of disease and improve the external validity of results.”

He reported having no financial disclosures.
 

dbrunk@frontlinemedcom.com

 

CHICAGO – There is considerable variability and poor documentation of severity assessments used for inclusion criteria and baseline severity evaluations in randomized, controlled pediatric atopic dermatitis (AD) trials, results from a systematic review showed.

“It is important for clinicians and investigators to recognize that these differences may limit our ability to reproduce trials, interpret individual studies, and compare results between studies of similar target populations for severity,” lead study author Rishi Chopra, MS, said in an interview in advance of the World Congress of Pediatric Dermatology. “Moreover, this heterogeneity should be considered when retroactively pooling results for meta-analyses of pediatric atopic dermatitis randomized, controlled trials.”

According to Mr. Chopra, a fourth-year medical student at the State University of New York at Stony Brook and visiting predoctoral research fellow in the department of dermatology at Northwestern University, Chicago, clinician assessments of AD may be subjective, inaccurate, and difficult to standardize. Consequently, objective severity scoring assessments were developed to accurately quantitate and communicate disease burden. “However, there are now more than 60 of these unique severity assessments, fewer than 20 have undergone preliminary validation, and only 3 are sufficiently validated and recommended for use,” he said. “This represents a huge challenge for clinical trials as the combination of inadequately validated assessments and heterogeneity in assessment used in clinical trials may prevent both the accurate interpretation of results within an individual trial and comparison of interventions amongst trials.”

In an effort to evaluate the documentation and characterize the severity assessments used in inclusion criteria and baseline evaluations for randomized, controlled trials of pediatric AD internationally, the researchers performed a systematic review of relevant studies contained in the Cochrane Library, Embase, LILACS, GREAT, MEDLINE, and Scopus databases during 2007-2016. Inclusion criteria were RCT with a pharmacological intervention and any comparison with a control group, children, and males or females. In all, 89 studies met the inclusion/exclusion criteria. Most (70.8%) were studies of pediatric populations aged 0-17 years, and almost 17% were studies of infants aged 0-1 years. The most common target populations were mild-moderate AD (31.5%), moderate-severe AD (18.0%), or undefined (36.0%).

Mr. Chopra and his associates found that the most commonly used severity indices were Scoring AD (SCORAD) in 29.2%, Body Surface Area (BSA) in 16.9%, and global assessments in 13.4%, while the most common assessments of baseline severity were SCORAD in 43.8%, global assessments in 20.2%, Eczema Area and Severity Index in 17.9%, BSA in 14.6%, and visual itch in 13.5%. Only 85.4% of studies recorded the severity assessments used for recruiting the predefined target population and only 76.4% of studies documented baseline severity.

There was considerable heterogeneity across studies, as 16 unique assessments were used as inclusion criteria and 34 assessments were used to evaluate baseline severity. “In addition, even within an individual study, there was substantial discordance in their use as only 71.2% of studies used the same assessments for inclusion and documenting baseline disease severity,” Mr. Chopra said. “Altogether, this multidimensional lack of documentation and heterogeneity of inclusion criteria and baseline severity assessments limits our ability to assess whether the recruitment methods for patients were adequate and confirm whether the intended target population for severity was successfully enrolled.”

He acknowledged certain limitations of the study, including the fact that it may not be generalizable to nonpharmacological interventional trials or noninterventional studies. “In addition, we could only conduct an analysis for studies that provided adequate documentation of inclusion criteria and baseline severity,” Mr. Chopra said. “Thus, those studies that did not provide this information were left out. Nevertheless, across all studies, the uniformity and concordance between assessments likely are even more negatively impacted. It should also be noted that lack of documentation of assessments for inclusion criteria and baseline severity does not imply lack of their utilization. Finally, it is important to acknowledge that AD’s diverse phenotype and relapsing and remitting course may result in the unavoidable heterogeneity of severity assessment use. This may actually help to capture a broader range of disease and improve the external validity of results.”

He reported having no financial disclosures.
 

dbrunk@frontlinemedcom.com

The prevalence of topical cannabinoids has risen sharply in recent years. Commercial advertisers promote their usage as a safe means to treat a multitude of skin disorders, including atopic dermatitis (AD), psoriasis, and acne. Topical compounds have garnered interest in laboratory studies, but the purchase of commercial formulations is limited to over-the-counter products from unregulated suppliers. In this article, we review the scientific evidence behind topical cannabinoids and evaluate their role in clinical dermatology.

Background

Cannabis is designated as a Schedule I drug, according to the Controlled Substances Act of 1970. This listing is given to substances with no therapeutic value and a high potential for abuse. However, as of 2017, 29 states and the District of Columbia have laws legalizing cannabis in some capacity. These regulations typically apply to medicinal use, though several states have now legalized recreational use.

Cannabinoids represent a broad class of chemical compounds derived from the cannabis plant. Originally, this class only comprised phytocannabinoids, cannabinoids produced by the cannabis plant. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and leads to the psychoactive effects typically associated with cannabis use. Later investigation led to the discovery of endocannabinoids, cannabinoids that are naturally produced by human and animal bodies, as well as synthetic cannabinoids.¹ Cannabidiol is a phytocannabinoid that has been investigated in neurologic and anti-inflammatory conditions.^2-4

Cannabinoids act as agonists on 2 principal receptors— cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)—which are both G protein–coupled receptors (Figure).⁵ Both have distinct distributions throughout different organ systems, to which cannabinoids (eg, THC, cannabidiol, endocannabinoids) show differential binding.^6,7 Importantly, the expression of CB1 and CB2 has been identified on sensory nerve fibers, inflammatory cells, and adnexal structures of human skin.⁸ Based on these associations, topical application of cannabinoids has become a modality of interest for dermatological disorders. These formulations aim to influence cutaneous morphology without producing psychoactive effects.

Topical Cannabinoids in Inflammatory Disorders

Atopic dermatitis has emerged as an active area of investigation for cannabinoid receptors and topical agonists (Table 1). In an animal model, Kim et al⁹ examined the effects of CB1 agonism on skin inflammation. Mice treated with topical CB1 agonists showed greater recovery of epidermal barrier function in acutely abrogated skin relative to those treated with a vehicle preparation. In addition, agonism of CB1 led to significant (P<.001) decreases in skin fold thickness among models of acute and chronic skin inflammation.⁹

Nam et al¹⁰ also examined the role of topical CB1 agonists in mice with induced AD-like symptoms. Relative to treatment with vehicle, CB1 agonists significantly reduced the recruitment of mast cells (P<.01) and lowered the blood concentration of histamine (P<.05). Given the noted decrease in the release of inflammatory mediators, the authors speculated that topical agonsim of CB1 may prove useful in several conditions related to mast cell activation, such as AD, contact dermatitis, and psoriasis.¹⁰

The anti-inflammatory properties of topical THC were evaluated by Gaffal et al.¹¹ In a mouse model of allergic contact dermatitis, mice treated with topical THC showed decreases in myeloid immune cell infiltration, with these beneficial effects existing even in mice with deficient CB1 and CB2 receptors. These results support a potentially wide anti-inflammatory activity of topical THC.¹¹

Topical Cannabinoids in Pain Management

The effects of smoked cannabis in treating pain have undergone thorough investigation over recent years. Benefits have been noted in treating neuropathic pain, particularly in human immunodeficiency virus–associated sensory neuropathy.^12-15 Smoked cannabis also may provide value as a synergistic therapy with opioids, thereby allowing for lower opioid doses.¹⁶

In contrast, research into the relationship between topical application of cannabinoids and nociception remains in preliminary stages (Table 2). In a mouse model, Dogrul et al¹⁷ assessed the topical antinociceptive potential of a mixed CB1-CB2 agonist. Results showed significant (P<.01) and dose-dependent antinociceptive effects relative to treatment with a vehicle.¹⁷ In a related study, Yesilyurt et al¹⁸ evaluated whether a mixed CB1-CB2 agonist could enhance the antinociceptive effects of topical opioids. Among mice treated with the combination of a cannabinoid agonist and topical morphine, a significantly (P<.05) greater analgesic effect was demonstrated relative to topical morphine alone.¹⁸

Studies in humans have been far more limited. Phan et al¹⁹ conducted a small, nonrandomized, open-label trial of a topical cannabinoid cream in patients with facial postherpetic neuralgia. Of 8 patients treated, 5 noted a mean pain reduction of 87.8%. No comparison vehicle was used. Based on this narrow study design, it is difficult to extrapolate these positive results to a broader patient population.¹⁹

 

Commercial Products

Although preliminary models with topical cannabinoids have shown potential, large-scale clinical trials in humans have yet to be performed. Despite this lack of investigation, commercial formulations of topical cannabinoids are available to dermatology patients. These formulations are nonstandardized, and no safety data exists regarding their use. Topical cannabinoids on the market may contain various amounts of active ingredient and may be combined with a range of other compounds.

In dermatology offices, it is not uncommon for patients to express an intention to use topical cannabinoid products following their planned treatment or procedure. Patients also have been known to use topical cannabinoid products prior to dermatologic procedures, sometimes in place of an approved topical anesthetic, without consulting the physician performing the procedure. With interventions that lead to active areas of wound healing, the application of such products may increase the risk for contamination and infection. Therefore, patients should be counseled that the use of commercial topical cannabinoids could jeopardize the success of their planned procedure, put them at risk for infection, and possibly lead to systemic absorption and/or changes in wound-healing capacities.

Conclusion

Based on the results from recent animal models, cannabinoids may have a role in future treatment algorithms for several inflammatory conditions. However, current efficacy and safety data are almost entirely limited to preliminary animal studies in rodents. In addition, the formulation of topical cannabinoid products is nonstandardized and poorly regulated. As such, the present evidence does not support the use of topical cannabinoids in dermatology practices. Dermatologists should ask patients about the use of any cannabinoid products as part of a treatment program, especially given the unsubstantiated claims often made by unscrupulous advertisers. This issue highlights the need for further research and regulation.

The prevalence of topical cannabinoids has risen sharply in recent years. Commercial advertisers promote their usage as a safe means to treat a multitude of skin disorders, including atopic dermatitis (AD), psoriasis, and acne. Topical compounds have garnered interest in laboratory studies, but the purchase of commercial formulations is limited to over-the-counter products from unregulated suppliers. In this article, we review the scientific evidence behind topical cannabinoids and evaluate their role in clinical dermatology.

Background

Cannabis is designated as a Schedule I drug, according to the Controlled Substances Act of 1970. This listing is given to substances with no therapeutic value and a high potential for abuse. However, as of 2017, 29 states and the District of Columbia have laws legalizing cannabis in some capacity. These regulations typically apply to medicinal use, though several states have now legalized recreational use.

Cannabinoids represent a broad class of chemical compounds derived from the cannabis plant. Originally, this class only comprised phytocannabinoids, cannabinoids produced by the cannabis plant. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and leads to the psychoactive effects typically associated with cannabis use. Later investigation led to the discovery of endocannabinoids, cannabinoids that are naturally produced by human and animal bodies, as well as synthetic cannabinoids.¹ Cannabidiol is a phytocannabinoid that has been investigated in neurologic and anti-inflammatory conditions.^2-4

Cannabinoids act as agonists on 2 principal receptors— cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)—which are both G protein–coupled receptors (Figure).⁵ Both have distinct distributions throughout different organ systems, to which cannabinoids (eg, THC, cannabidiol, endocannabinoids) show differential binding.^6,7 Importantly, the expression of CB1 and CB2 has been identified on sensory nerve fibers, inflammatory cells, and adnexal structures of human skin.⁸ Based on these associations, topical application of cannabinoids has become a modality of interest for dermatological disorders. These formulations aim to influence cutaneous morphology without producing psychoactive effects.

Topical Cannabinoids in Inflammatory Disorders

Atopic dermatitis has emerged as an active area of investigation for cannabinoid receptors and topical agonists (Table 1). In an animal model, Kim et al⁹ examined the effects of CB1 agonism on skin inflammation. Mice treated with topical CB1 agonists showed greater recovery of epidermal barrier function in acutely abrogated skin relative to those treated with a vehicle preparation. In addition, agonism of CB1 led to significant (P<.001) decreases in skin fold thickness among models of acute and chronic skin inflammation.⁹

Nam et al¹⁰ also examined the role of topical CB1 agonists in mice with induced AD-like symptoms. Relative to treatment with vehicle, CB1 agonists significantly reduced the recruitment of mast cells (P<.01) and lowered the blood concentration of histamine (P<.05). Given the noted decrease in the release of inflammatory mediators, the authors speculated that topical agonsim of CB1 may prove useful in several conditions related to mast cell activation, such as AD, contact dermatitis, and psoriasis.¹⁰

The anti-inflammatory properties of topical THC were evaluated by Gaffal et al.¹¹ In a mouse model of allergic contact dermatitis, mice treated with topical THC showed decreases in myeloid immune cell infiltration, with these beneficial effects existing even in mice with deficient CB1 and CB2 receptors. These results support a potentially wide anti-inflammatory activity of topical THC.¹¹

Topical Cannabinoids in Pain Management

The effects of smoked cannabis in treating pain have undergone thorough investigation over recent years. Benefits have been noted in treating neuropathic pain, particularly in human immunodeficiency virus–associated sensory neuropathy.^12-15 Smoked cannabis also may provide value as a synergistic therapy with opioids, thereby allowing for lower opioid doses.¹⁶

In contrast, research into the relationship between topical application of cannabinoids and nociception remains in preliminary stages (Table 2). In a mouse model, Dogrul et al¹⁷ assessed the topical antinociceptive potential of a mixed CB1-CB2 agonist. Results showed significant (P<.01) and dose-dependent antinociceptive effects relative to treatment with a vehicle.¹⁷ In a related study, Yesilyurt et al¹⁸ evaluated whether a mixed CB1-CB2 agonist could enhance the antinociceptive effects of topical opioids. Among mice treated with the combination of a cannabinoid agonist and topical morphine, a significantly (P<.05) greater analgesic effect was demonstrated relative to topical morphine alone.¹⁸

Studies in humans have been far more limited. Phan et al¹⁹ conducted a small, nonrandomized, open-label trial of a topical cannabinoid cream in patients with facial postherpetic neuralgia. Of 8 patients treated, 5 noted a mean pain reduction of 87.8%. No comparison vehicle was used. Based on this narrow study design, it is difficult to extrapolate these positive results to a broader patient population.¹⁹

 

Commercial Products

Although preliminary models with topical cannabinoids have shown potential, large-scale clinical trials in humans have yet to be performed. Despite this lack of investigation, commercial formulations of topical cannabinoids are available to dermatology patients. These formulations are nonstandardized, and no safety data exists regarding their use. Topical cannabinoids on the market may contain various amounts of active ingredient and may be combined with a range of other compounds.

In dermatology offices, it is not uncommon for patients to express an intention to use topical cannabinoid products following their planned treatment or procedure. Patients also have been known to use topical cannabinoid products prior to dermatologic procedures, sometimes in place of an approved topical anesthetic, without consulting the physician performing the procedure. With interventions that lead to active areas of wound healing, the application of such products may increase the risk for contamination and infection. Therefore, patients should be counseled that the use of commercial topical cannabinoids could jeopardize the success of their planned procedure, put them at risk for infection, and possibly lead to systemic absorption and/or changes in wound-healing capacities.

Conclusion

Based on the results from recent animal models, cannabinoids may have a role in future treatment algorithms for several inflammatory conditions. However, current efficacy and safety data are almost entirely limited to preliminary animal studies in rodents. In addition, the formulation of topical cannabinoid products is nonstandardized and poorly regulated. As such, the present evidence does not support the use of topical cannabinoids in dermatology practices. Dermatologists should ask patients about the use of any cannabinoid products as part of a treatment program, especially given the unsubstantiated claims often made by unscrupulous advertisers. This issue highlights the need for further research and regulation.

The prevalence of topical cannabinoids has risen sharply in recent years. Commercial advertisers promote their usage as a safe means to treat a multitude of skin disorders, including atopic dermatitis (AD), psoriasis, and acne. Topical compounds have garnered interest in laboratory studies, but the purchase of commercial formulations is limited to over-the-counter products from unregulated suppliers. In this article, we review the scientific evidence behind topical cannabinoids and evaluate their role in clinical dermatology.

Background

Cannabis is designated as a Schedule I drug, according to the Controlled Substances Act of 1970. This listing is given to substances with no therapeutic value and a high potential for abuse. However, as of 2017, 29 states and the District of Columbia have laws legalizing cannabis in some capacity. These regulations typically apply to medicinal use, though several states have now legalized recreational use.

Cannabinoids represent a broad class of chemical compounds derived from the cannabis plant. Originally, this class only comprised phytocannabinoids, cannabinoids produced by the cannabis plant. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and leads to the psychoactive effects typically associated with cannabis use. Later investigation led to the discovery of endocannabinoids, cannabinoids that are naturally produced by human and animal bodies, as well as synthetic cannabinoids.¹ Cannabidiol is a phytocannabinoid that has been investigated in neurologic and anti-inflammatory conditions.^2-4

Cannabinoids act as agonists on 2 principal receptors— cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)—which are both G protein–coupled receptors (Figure).⁵ Both have distinct distributions throughout different organ systems, to which cannabinoids (eg, THC, cannabidiol, endocannabinoids) show differential binding.^6,7 Importantly, the expression of CB1 and CB2 has been identified on sensory nerve fibers, inflammatory cells, and adnexal structures of human skin.⁸ Based on these associations, topical application of cannabinoids has become a modality of interest for dermatological disorders. These formulations aim to influence cutaneous morphology without producing psychoactive effects.

Topical Cannabinoids in Inflammatory Disorders

Atopic dermatitis has emerged as an active area of investigation for cannabinoid receptors and topical agonists (Table 1). In an animal model, Kim et al⁹ examined the effects of CB1 agonism on skin inflammation. Mice treated with topical CB1 agonists showed greater recovery of epidermal barrier function in acutely abrogated skin relative to those treated with a vehicle preparation. In addition, agonism of CB1 led to significant (P<.001) decreases in skin fold thickness among models of acute and chronic skin inflammation.⁹

Nam et al¹⁰ also examined the role of topical CB1 agonists in mice with induced AD-like symptoms. Relative to treatment with vehicle, CB1 agonists significantly reduced the recruitment of mast cells (P<.01) and lowered the blood concentration of histamine (P<.05). Given the noted decrease in the release of inflammatory mediators, the authors speculated that topical agonsim of CB1 may prove useful in several conditions related to mast cell activation, such as AD, contact dermatitis, and psoriasis.¹⁰

The anti-inflammatory properties of topical THC were evaluated by Gaffal et al.¹¹ In a mouse model of allergic contact dermatitis, mice treated with topical THC showed decreases in myeloid immune cell infiltration, with these beneficial effects existing even in mice with deficient CB1 and CB2 receptors. These results support a potentially wide anti-inflammatory activity of topical THC.¹¹

Topical Cannabinoids in Pain Management

The effects of smoked cannabis in treating pain have undergone thorough investigation over recent years. Benefits have been noted in treating neuropathic pain, particularly in human immunodeficiency virus–associated sensory neuropathy.^12-15 Smoked cannabis also may provide value as a synergistic therapy with opioids, thereby allowing for lower opioid doses.¹⁶

In contrast, research into the relationship between topical application of cannabinoids and nociception remains in preliminary stages (Table 2). In a mouse model, Dogrul et al¹⁷ assessed the topical antinociceptive potential of a mixed CB1-CB2 agonist. Results showed significant (P<.01) and dose-dependent antinociceptive effects relative to treatment with a vehicle.¹⁷ In a related study, Yesilyurt et al¹⁸ evaluated whether a mixed CB1-CB2 agonist could enhance the antinociceptive effects of topical opioids. Among mice treated with the combination of a cannabinoid agonist and topical morphine, a significantly (P<.05) greater analgesic effect was demonstrated relative to topical morphine alone.¹⁸

Studies in humans have been far more limited. Phan et al¹⁹ conducted a small, nonrandomized, open-label trial of a topical cannabinoid cream in patients with facial postherpetic neuralgia. Of 8 patients treated, 5 noted a mean pain reduction of 87.8%. No comparison vehicle was used. Based on this narrow study design, it is difficult to extrapolate these positive results to a broader patient population.¹⁹

 

Commercial Products

Although preliminary models with topical cannabinoids have shown potential, large-scale clinical trials in humans have yet to be performed. Despite this lack of investigation, commercial formulations of topical cannabinoids are available to dermatology patients. These formulations are nonstandardized, and no safety data exists regarding their use. Topical cannabinoids on the market may contain various amounts of active ingredient and may be combined with a range of other compounds.

In dermatology offices, it is not uncommon for patients to express an intention to use topical cannabinoid products following their planned treatment or procedure. Patients also have been known to use topical cannabinoid products prior to dermatologic procedures, sometimes in place of an approved topical anesthetic, without consulting the physician performing the procedure. With interventions that lead to active areas of wound healing, the application of such products may increase the risk for contamination and infection. Therefore, patients should be counseled that the use of commercial topical cannabinoids could jeopardize the success of their planned procedure, put them at risk for infection, and possibly lead to systemic absorption and/or changes in wound-healing capacities.

Conclusion

Based on the results from recent animal models, cannabinoids may have a role in future treatment algorithms for several inflammatory conditions. However, current efficacy and safety data are almost entirely limited to preliminary animal studies in rodents. In addition, the formulation of topical cannabinoid products is nonstandardized and poorly regulated. As such, the present evidence does not support the use of topical cannabinoids in dermatology practices. Dermatologists should ask patients about the use of any cannabinoid products as part of a treatment program, especially given the unsubstantiated claims often made by unscrupulous advertisers. This issue highlights the need for further research and regulation.

 

Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

Courtesy National Institute of Allergy and Infectious Diseases

The patients carried a mutation in just one copy of the gene, while the remaining copy was normal, which was a surprise given the severity of the disease (Nat Genet. 2017 Jun 19. doi: 10.1038/ng.3898). “You would expect to have a mutation on both alleles, not just one,” in patients with such severe disease, said Josh D. Milner, MD, one of the senior authors and chief of the genetics and pathogenesis of allergy section in the NIAID’s Laboratory of Allergic Diseases.

When the mutated genes were inserted into T cells, the researchers found that the mutated copy of the gene interfered with the normal copy, preventing the activation of NF-kB and mTORC1 (mammalian target of rapamycin complex 1) – effects that may contribute to the severity of AD in these patients.

The results could have broad-ranging clinical implications, Dr. Milner said in an interview. CARD11 has been shown to be associated with AD in previous genomewide association studies. “It may not be the case that this is just found in a few rare families. This could potentially be a gene or pathway that could explain a lot of atopic dermatitis,” he noted.

The study results also point to a potential therapy for AD. The pathway can lead to a deficiency in glutamine uptake into cells, and the study suggests that glutamine supplementation could potentially restore some cells to normal functioning.

Dr. Milner also pointed out that glutamine deficiency could be an indirect consequence of the disease. “Kids with bad allergic disease are usually on a poor diet because they are avoiding foods. They may not be getting enough protein intake,” he said.

In fact, a prevention trial in premature infants sought to determine if glutamine supplementation could reduce infections. The primary endpoint failed, but researchers noted a reduction in AD, according to Dr. Milner. “That’s pretty amazing, given what we just found.”

This study is among recent studies that have highlighted potential targets for treatment of AD, including one reporting that tumor necrosis factor–like weak inducer of apoptosis, a protein, may be involved in both AD and psoriasis (Nat Commun. 2017 May 22;8:15395.).

Research identifying novel pathways involved in AD led to the development of dupilumab, which targets interleukin-4 and interleukin-13 and was recently approved by the Food and Drug Administration for moderate to severe AD. It is the first targeted biologic therapy to become available for AD. “I can’t underscore the importance of dupilumab enough,” Dr. Milner commented.

He and the other authors had no related disclosures.

 

Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

Courtesy National Institute of Allergy and Infectious Diseases

The patients carried a mutation in just one copy of the gene, while the remaining copy was normal, which was a surprise given the severity of the disease (Nat Genet. 2017 Jun 19. doi: 10.1038/ng.3898). “You would expect to have a mutation on both alleles, not just one,” in patients with such severe disease, said Josh D. Milner, MD, one of the senior authors and chief of the genetics and pathogenesis of allergy section in the NIAID’s Laboratory of Allergic Diseases.

When the mutated genes were inserted into T cells, the researchers found that the mutated copy of the gene interfered with the normal copy, preventing the activation of NF-kB and mTORC1 (mammalian target of rapamycin complex 1) – effects that may contribute to the severity of AD in these patients.

The results could have broad-ranging clinical implications, Dr. Milner said in an interview. CARD11 has been shown to be associated with AD in previous genomewide association studies. “It may not be the case that this is just found in a few rare families. This could potentially be a gene or pathway that could explain a lot of atopic dermatitis,” he noted.

The study results also point to a potential therapy for AD. The pathway can lead to a deficiency in glutamine uptake into cells, and the study suggests that glutamine supplementation could potentially restore some cells to normal functioning.

Dr. Milner also pointed out that glutamine deficiency could be an indirect consequence of the disease. “Kids with bad allergic disease are usually on a poor diet because they are avoiding foods. They may not be getting enough protein intake,” he said.

In fact, a prevention trial in premature infants sought to determine if glutamine supplementation could reduce infections. The primary endpoint failed, but researchers noted a reduction in AD, according to Dr. Milner. “That’s pretty amazing, given what we just found.”

This study is among recent studies that have highlighted potential targets for treatment of AD, including one reporting that tumor necrosis factor–like weak inducer of apoptosis, a protein, may be involved in both AD and psoriasis (Nat Commun. 2017 May 22;8:15395.).

Research identifying novel pathways involved in AD led to the development of dupilumab, which targets interleukin-4 and interleukin-13 and was recently approved by the Food and Drug Administration for moderate to severe AD. It is the first targeted biologic therapy to become available for AD. “I can’t underscore the importance of dupilumab enough,” Dr. Milner commented.

He and the other authors had no related disclosures.

 

Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

Courtesy National Institute of Allergy and Infectious Diseases

The patients carried a mutation in just one copy of the gene, while the remaining copy was normal, which was a surprise given the severity of the disease (Nat Genet. 2017 Jun 19. doi: 10.1038/ng.3898). “You would expect to have a mutation on both alleles, not just one,” in patients with such severe disease, said Josh D. Milner, MD, one of the senior authors and chief of the genetics and pathogenesis of allergy section in the NIAID’s Laboratory of Allergic Diseases.

When the mutated genes were inserted into T cells, the researchers found that the mutated copy of the gene interfered with the normal copy, preventing the activation of NF-kB and mTORC1 (mammalian target of rapamycin complex 1) – effects that may contribute to the severity of AD in these patients.

The results could have broad-ranging clinical implications, Dr. Milner said in an interview. CARD11 has been shown to be associated with AD in previous genomewide association studies. “It may not be the case that this is just found in a few rare families. This could potentially be a gene or pathway that could explain a lot of atopic dermatitis,” he noted.

The study results also point to a potential therapy for AD. The pathway can lead to a deficiency in glutamine uptake into cells, and the study suggests that glutamine supplementation could potentially restore some cells to normal functioning.

Dr. Milner also pointed out that glutamine deficiency could be an indirect consequence of the disease. “Kids with bad allergic disease are usually on a poor diet because they are avoiding foods. They may not be getting enough protein intake,” he said.

In fact, a prevention trial in premature infants sought to determine if glutamine supplementation could reduce infections. The primary endpoint failed, but researchers noted a reduction in AD, according to Dr. Milner. “That’s pretty amazing, given what we just found.”

This study is among recent studies that have highlighted potential targets for treatment of AD, including one reporting that tumor necrosis factor–like weak inducer of apoptosis, a protein, may be involved in both AD and psoriasis (Nat Commun. 2017 May 22;8:15395.).

Research identifying novel pathways involved in AD led to the development of dupilumab, which targets interleukin-4 and interleukin-13 and was recently approved by the Food and Drug Administration for moderate to severe AD. It is the first targeted biologic therapy to become available for AD. “I can’t underscore the importance of dupilumab enough,” Dr. Milner commented.

He and the other authors had no related disclosures.

 

An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.

New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.

“We always teach that these are very different diseases. Here, however, you have a very specific cytokine and its very specific receptor, and both are very important not just in initiating inflammation, but perpetuating it. The cytokines we talk about with these diseases actually require TWEAK and Fn14 to interact,” said Adam Friedman, MD, of the department of dermatology, and director of translational research at George Washington University, Washington, who was not involved in the study.

The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.

The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.

The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).

The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.

Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.

Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.

Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.

But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.

Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.

 

An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.

New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.

“We always teach that these are very different diseases. Here, however, you have a very specific cytokine and its very specific receptor, and both are very important not just in initiating inflammation, but perpetuating it. The cytokines we talk about with these diseases actually require TWEAK and Fn14 to interact,” said Adam Friedman, MD, of the department of dermatology, and director of translational research at George Washington University, Washington, who was not involved in the study.

The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.

The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.

The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).

The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.

Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.

Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.

Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.

But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.

Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.

 

An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.

New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.

“We always teach that these are very different diseases. Here, however, you have a very specific cytokine and its very specific receptor, and both are very important not just in initiating inflammation, but perpetuating it. The cytokines we talk about with these diseases actually require TWEAK and Fn14 to interact,” said Adam Friedman, MD, of the department of dermatology, and director of translational research at George Washington University, Washington, who was not involved in the study.

The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.

The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.

The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).

The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.

Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.

Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.

Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.

But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.

Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.

 

“Therapeutic patient education” (TPE) is a new paradigm that addresses less than optimal outcomes in patients with atopic dermatitis (AD) resulting from poor adherence to treatment.

The aim of TPE, a multidisciplinary approach to caring for and managing AD, is to improve patient and caregiver adherence to physician-directed treatments through education and to improve quality of life, according to several presenters who spoke at a pediatric dermatology meeting sponsored by Rady Children’s Hospital–San Diego and University of California, San Diego. They reviewed the approach to using TPE in chronic disease states, demonstrating this state-of-the-art approach to educating patients, families, and health care providers about AD management, and allowing for the exchange of ideas for best practices on AD therapeutic education programs and use in the U.S. health care environment.

Other successful meetings on TPE in Europe, Asia, and South America inspired this meeting, the first in the United States aimed to train health care professionals in TPE principles for AD. The meeting was sponsored by the Fondation Dermatite Atopique (Atopic Dermatitis Foundation for Research and Education), Rady’s Eczema and Inflammatory Skin Disease Center, and UCSD.

TPE is defined by the World Health Organization as an approach to help patients with chronic illness acquire or maintain the skills necessary to manage their life and illness in the best way possible. TPE involves patient preferences, shared decision-making, organized activities, psychosocial support, hospital organization and procedures, and health- and disease-related behaviors.

Sébastien Barbarot, MD, of the departments of dermatology and pediatric dermatology, Nantes (France) University Hospital, said that there are four main components to the TPE process:

• Assessing and understanding the patient’s knowledge and values.

• Developing age-appropriate personalized educational objectives.

• Transferring the necessary skills to the patient or caregiver.

• Assessing the effectiveness of the educational program.

Lawrence Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego and professor of dermatology and pediatrics at UCSD, discussed how to conduct the initial visit with potential candidates for TPE. At the new patient visit, the pediatric patient and their caregivers should first be presented with the concept of TPE, which includes proposing a personalized education approach. Next, explain the goals and benefits of TPE (with a time and location for the sessions), provide educational materials, allow time for questions, and establish the patient’s consent to participate.

This process requires health care professionals to assess patient/caregiver knowledge, concerns, past experiences, and barriers to adherence. Based on these questions, providers should develop educational objectives in collaboration with the patient. The objectives should be tailored to the age of the patient and can be phrased in terms of “To be capable of.”

The certain skills that patients should acquire fall under three main categories: knowledge of the disease, practical skills, and relational skills.

Alain Golay, MD, professor and chief of the department of therapeutic education in chronic diseases at the Geneva University Hospital, said that patients and caregivers should be familiar with the pathophysiology and natural history of the disease, as well as with aggravating factors and the rationale behind elements of the treatment plan – and they should understand a reasonable timeline for treatment responses.

Learning how to properly apply the treatment is among the practical skills that the patient needs to acquire. In terms of relational skills, patients should know enough about their disease to be able to explain it to others. Educational methods can include interactive presentations, case studies, roundtable meetings, workshops, and role play. Other tools that can be used as a resource include written action plans, posters, informational videos, reminders, and booklets. Nurse-led educational sessions that increase teaching time is another modality. Multidisciplinary clinics should include an allergist, dermatologist, psychologist, dietitian, and nurse. These clinics also can form workshops or teaching groups. This allows for smaller groups where ideas can be exchanged, and can be targeted specifically based on the audiences’ needs, he said.

Dr. Barbarot outlined the fourth step of TPE, which involves assessment of effectiveness. Several outcome measures can be used, including clinical outcomes, quality of life, patient global assessment, and knowledge questionnaires.

dermnews@frontlinemedcom.com

 

“Therapeutic patient education” (TPE) is a new paradigm that addresses less than optimal outcomes in patients with atopic dermatitis (AD) resulting from poor adherence to treatment.

The aim of TPE, a multidisciplinary approach to caring for and managing AD, is to improve patient and caregiver adherence to physician-directed treatments through education and to improve quality of life, according to several presenters who spoke at a pediatric dermatology meeting sponsored by Rady Children’s Hospital–San Diego and University of California, San Diego. They reviewed the approach to using TPE in chronic disease states, demonstrating this state-of-the-art approach to educating patients, families, and health care providers about AD management, and allowing for the exchange of ideas for best practices on AD therapeutic education programs and use in the U.S. health care environment.

Other successful meetings on TPE in Europe, Asia, and South America inspired this meeting, the first in the United States aimed to train health care professionals in TPE principles for AD. The meeting was sponsored by the Fondation Dermatite Atopique (Atopic Dermatitis Foundation for Research and Education), Rady’s Eczema and Inflammatory Skin Disease Center, and UCSD.

TPE is defined by the World Health Organization as an approach to help patients with chronic illness acquire or maintain the skills necessary to manage their life and illness in the best way possible. TPE involves patient preferences, shared decision-making, organized activities, psychosocial support, hospital organization and procedures, and health- and disease-related behaviors.

Sébastien Barbarot, MD, of the departments of dermatology and pediatric dermatology, Nantes (France) University Hospital, said that there are four main components to the TPE process:

• Assessing and understanding the patient’s knowledge and values.

• Developing age-appropriate personalized educational objectives.

• Transferring the necessary skills to the patient or caregiver.

• Assessing the effectiveness of the educational program.

Lawrence Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego and professor of dermatology and pediatrics at UCSD, discussed how to conduct the initial visit with potential candidates for TPE. At the new patient visit, the pediatric patient and their caregivers should first be presented with the concept of TPE, which includes proposing a personalized education approach. Next, explain the goals and benefits of TPE (with a time and location for the sessions), provide educational materials, allow time for questions, and establish the patient’s consent to participate.

This process requires health care professionals to assess patient/caregiver knowledge, concerns, past experiences, and barriers to adherence. Based on these questions, providers should develop educational objectives in collaboration with the patient. The objectives should be tailored to the age of the patient and can be phrased in terms of “To be capable of.”

The certain skills that patients should acquire fall under three main categories: knowledge of the disease, practical skills, and relational skills.

Alain Golay, MD, professor and chief of the department of therapeutic education in chronic diseases at the Geneva University Hospital, said that patients and caregivers should be familiar with the pathophysiology and natural history of the disease, as well as with aggravating factors and the rationale behind elements of the treatment plan – and they should understand a reasonable timeline for treatment responses.

Learning how to properly apply the treatment is among the practical skills that the patient needs to acquire. In terms of relational skills, patients should know enough about their disease to be able to explain it to others. Educational methods can include interactive presentations, case studies, roundtable meetings, workshops, and role play. Other tools that can be used as a resource include written action plans, posters, informational videos, reminders, and booklets. Nurse-led educational sessions that increase teaching time is another modality. Multidisciplinary clinics should include an allergist, dermatologist, psychologist, dietitian, and nurse. These clinics also can form workshops or teaching groups. This allows for smaller groups where ideas can be exchanged, and can be targeted specifically based on the audiences’ needs, he said.

Dr. Barbarot outlined the fourth step of TPE, which involves assessment of effectiveness. Several outcome measures can be used, including clinical outcomes, quality of life, patient global assessment, and knowledge questionnaires.

dermnews@frontlinemedcom.com

 

“Therapeutic patient education” (TPE) is a new paradigm that addresses less than optimal outcomes in patients with atopic dermatitis (AD) resulting from poor adherence to treatment.

The aim of TPE, a multidisciplinary approach to caring for and managing AD, is to improve patient and caregiver adherence to physician-directed treatments through education and to improve quality of life, according to several presenters who spoke at a pediatric dermatology meeting sponsored by Rady Children’s Hospital–San Diego and University of California, San Diego. They reviewed the approach to using TPE in chronic disease states, demonstrating this state-of-the-art approach to educating patients, families, and health care providers about AD management, and allowing for the exchange of ideas for best practices on AD therapeutic education programs and use in the U.S. health care environment.

Other successful meetings on TPE in Europe, Asia, and South America inspired this meeting, the first in the United States aimed to train health care professionals in TPE principles for AD. The meeting was sponsored by the Fondation Dermatite Atopique (Atopic Dermatitis Foundation for Research and Education), Rady’s Eczema and Inflammatory Skin Disease Center, and UCSD.

TPE is defined by the World Health Organization as an approach to help patients with chronic illness acquire or maintain the skills necessary to manage their life and illness in the best way possible. TPE involves patient preferences, shared decision-making, organized activities, psychosocial support, hospital organization and procedures, and health- and disease-related behaviors.

Sébastien Barbarot, MD, of the departments of dermatology and pediatric dermatology, Nantes (France) University Hospital, said that there are four main components to the TPE process:

• Assessing and understanding the patient’s knowledge and values.

• Developing age-appropriate personalized educational objectives.

• Transferring the necessary skills to the patient or caregiver.

• Assessing the effectiveness of the educational program.

Lawrence Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego and professor of dermatology and pediatrics at UCSD, discussed how to conduct the initial visit with potential candidates for TPE. At the new patient visit, the pediatric patient and their caregivers should first be presented with the concept of TPE, which includes proposing a personalized education approach. Next, explain the goals and benefits of TPE (with a time and location for the sessions), provide educational materials, allow time for questions, and establish the patient’s consent to participate.

This process requires health care professionals to assess patient/caregiver knowledge, concerns, past experiences, and barriers to adherence. Based on these questions, providers should develop educational objectives in collaboration with the patient. The objectives should be tailored to the age of the patient and can be phrased in terms of “To be capable of.”

The certain skills that patients should acquire fall under three main categories: knowledge of the disease, practical skills, and relational skills.

Alain Golay, MD, professor and chief of the department of therapeutic education in chronic diseases at the Geneva University Hospital, said that patients and caregivers should be familiar with the pathophysiology and natural history of the disease, as well as with aggravating factors and the rationale behind elements of the treatment plan – and they should understand a reasonable timeline for treatment responses.

Learning how to properly apply the treatment is among the practical skills that the patient needs to acquire. In terms of relational skills, patients should know enough about their disease to be able to explain it to others. Educational methods can include interactive presentations, case studies, roundtable meetings, workshops, and role play. Other tools that can be used as a resource include written action plans, posters, informational videos, reminders, and booklets. Nurse-led educational sessions that increase teaching time is another modality. Multidisciplinary clinics should include an allergist, dermatologist, psychologist, dietitian, and nurse. These clinics also can form workshops or teaching groups. This allows for smaller groups where ideas can be exchanged, and can be targeted specifically based on the audiences’ needs, he said.

Dr. Barbarot outlined the fourth step of TPE, which involves assessment of effectiveness. Several outcome measures can be used, including clinical outcomes, quality of life, patient global assessment, and knowledge questionnaires.

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Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

 

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

 

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

 

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

 

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

 

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

 

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

 

A friend sent me an article from the New Yorker called “The Algorithm Will See You Now,” in which Siddhartha Mukherjee, MD, author of the magisterial “The Emperor of All Maladies,” ponders the effect artificial intelligence may have on medicine. One possible outcome may be that computers replace radiologists and dermatologists. (They already beat top humans at Jeopardy, chess, and Go, so why not lick Homo sapiens at pattern recognition?)

No worries for me. When Watson takes over, I will be off somewhere playing shuffleboard.

During his research, Dr. Mukherjee shadowed a dermatologist, one of whose patients presented with facial seborrheic dermatitis. The dermatologist told her patient:

“It’s a particularly bad case. But, the question is why it appeared now, and why it’s getting worse.” She asked the patient about new hair products or family stress. The man said he’d just lost his job.

“Keep a diary,” she advised. “We can determine if there’s a link.”

Thus was my pedagogic legacy shattered in an instant. I’ve spent decades advising students not to tell patients they have a bad case of anything and never to ask them to keep diaries. Then, a foremost medical writer in a leading cultural journal endorses the reverse of both lessons. What was I thinking all these years?

I counseled students not to call any case “bad” because I saw how patients took it personally if I told them that. No matter how mild their diagnosis – rosacea and seborrhea, maladies less emperors than footmen– patients who heard theirs called “bad” looked sad, even insulted. Sad and insulted patients may give up and don’t follow treatment advice. (With such a bad case, why bother?) I didn’t urge patients to think that way. I just couldn’t ignore that they did. By contrast, assuring people that their case “wasn’t bad at all!” made them light up like Halloween pumpkins.

As for diaries, I’ve filed a few that patients handed me over the years. I showed these detailed chronicles to students to illustrate the lengths to which people will go to explain the unexplainable, like the ups and downs of idiopathic urticaria, eczema, and so forth:
 

• Thursday, August 6th, had sushi at a restaurant with friends.
• Sunday, September 3rd, watched science-fiction movie, unable to sleep that night.
• Monday, October 2nd, discarded fourth new detergent.

And so on.

In the meantime, several times each working day patients would troop in with randomly reoccurring conditions, atopic dermatitis above all, prompting dialogues like these:

“This is crazy! I never had anything like this before!”

“Well, actually, Ms. Jones, I treated you for the same thing in 2006.”

*********************

“This is bizarre! I never had this, and no one in my family ever did either.”

“I see. Well, here’s a prescription.”

“Come to think of it, my Mom had sensitive skin, and I get these dry patches on my arms and legs every winter.”

********************

“I’ve changed my soap three times and thrown out my makeup four times, and the rash keeps coming back. What should I do?”

“Stop throwing out your soap and makeup?”

And so on and on.

Sometimes, of course, semi-plausible causes seem to surface, such as stress. The question is, How useful is it to point this out? Consider the New Yorker case. Once the doctor “determined there is a link,” how might the conversation go?

“We have found the trigger, Mr. Smith. It’s stress.”

“Great! What should I do?”

“Don’t get laid off.”

No doctor (I hope) would ever say that, but patients present reports like the following all the time:

“As a kid, I was allergic to milk, but I’m not anymore.” (No, he wasn’t – he had infantile eczema that got blamed on milk.)

“Penicillin gave me hives.” (But, the hives lasted 6 weeks after the penicillin was stopped, which showed that the hives were idiopathic.)

“I’m very sensitive. I can’t use any moisturizer, any makeup, or all pills.” (People generate long litanies of sensitivities, piling one spurious correlation on another.)

Who benefits from “determining the link” when there isn’t any? Not the patients I’ve been seeing for forty years. Your patients? Maybe detergent manufacturers?

As to my errant pedagogy, with any luck, my students don’t remember a word I told them, a safe assumption for any teacher.

Either that or they don’t read the New Yorker.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@frontlinemedcom.com.

 

A friend sent me an article from the New Yorker called “The Algorithm Will See You Now,” in which Siddhartha Mukherjee, MD, author of the magisterial “The Emperor of All Maladies,” ponders the effect artificial intelligence may have on medicine. One possible outcome may be that computers replace radiologists and dermatologists. (They already beat top humans at Jeopardy, chess, and Go, so why not lick Homo sapiens at pattern recognition?)

No worries for me. When Watson takes over, I will be off somewhere playing shuffleboard.

During his research, Dr. Mukherjee shadowed a dermatologist, one of whose patients presented with facial seborrheic dermatitis. The dermatologist told her patient:

“It’s a particularly bad case. But, the question is why it appeared now, and why it’s getting worse.” She asked the patient about new hair products or family stress. The man said he’d just lost his job.

“Keep a diary,” she advised. “We can determine if there’s a link.”

Thus was my pedagogic legacy shattered in an instant. I’ve spent decades advising students not to tell patients they have a bad case of anything and never to ask them to keep diaries. Then, a foremost medical writer in a leading cultural journal endorses the reverse of both lessons. What was I thinking all these years?

I counseled students not to call any case “bad” because I saw how patients took it personally if I told them that. No matter how mild their diagnosis – rosacea and seborrhea, maladies less emperors than footmen– patients who heard theirs called “bad” looked sad, even insulted. Sad and insulted patients may give up and don’t follow treatment advice. (With such a bad case, why bother?) I didn’t urge patients to think that way. I just couldn’t ignore that they did. By contrast, assuring people that their case “wasn’t bad at all!” made them light up like Halloween pumpkins.

As for diaries, I’ve filed a few that patients handed me over the years. I showed these detailed chronicles to students to illustrate the lengths to which people will go to explain the unexplainable, like the ups and downs of idiopathic urticaria, eczema, and so forth:
 

• Thursday, August 6th, had sushi at a restaurant with friends.
• Sunday, September 3rd, watched science-fiction movie, unable to sleep that night.
• Monday, October 2nd, discarded fourth new detergent.

And so on.

In the meantime, several times each working day patients would troop in with randomly reoccurring conditions, atopic dermatitis above all, prompting dialogues like these:

“This is crazy! I never had anything like this before!”

“Well, actually, Ms. Jones, I treated you for the same thing in 2006.”

*********************

“This is bizarre! I never had this, and no one in my family ever did either.”

“I see. Well, here’s a prescription.”

“Come to think of it, my Mom had sensitive skin, and I get these dry patches on my arms and legs every winter.”

********************

“I’ve changed my soap three times and thrown out my makeup four times, and the rash keeps coming back. What should I do?”

“Stop throwing out your soap and makeup?”

And so on and on.

Sometimes, of course, semi-plausible causes seem to surface, such as stress. The question is, How useful is it to point this out? Consider the New Yorker case. Once the doctor “determined there is a link,” how might the conversation go?

“We have found the trigger, Mr. Smith. It’s stress.”

“Great! What should I do?”

“Don’t get laid off.”

No doctor (I hope) would ever say that, but patients present reports like the following all the time:

“As a kid, I was allergic to milk, but I’m not anymore.” (No, he wasn’t – he had infantile eczema that got blamed on milk.)

“Penicillin gave me hives.” (But, the hives lasted 6 weeks after the penicillin was stopped, which showed that the hives were idiopathic.)

“I’m very sensitive. I can’t use any moisturizer, any makeup, or all pills.” (People generate long litanies of sensitivities, piling one spurious correlation on another.)

Who benefits from “determining the link” when there isn’t any? Not the patients I’ve been seeing for forty years. Your patients? Maybe detergent manufacturers?

As to my errant pedagogy, with any luck, my students don’t remember a word I told them, a safe assumption for any teacher.

Either that or they don’t read the New Yorker.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@frontlinemedcom.com.

 

A friend sent me an article from the New Yorker called “The Algorithm Will See You Now,” in which Siddhartha Mukherjee, MD, author of the magisterial “The Emperor of All Maladies,” ponders the effect artificial intelligence may have on medicine. One possible outcome may be that computers replace radiologists and dermatologists. (They already beat top humans at Jeopardy, chess, and Go, so why not lick Homo sapiens at pattern recognition?)

No worries for me. When Watson takes over, I will be off somewhere playing shuffleboard.

During his research, Dr. Mukherjee shadowed a dermatologist, one of whose patients presented with facial seborrheic dermatitis. The dermatologist told her patient:

“It’s a particularly bad case. But, the question is why it appeared now, and why it’s getting worse.” She asked the patient about new hair products or family stress. The man said he’d just lost his job.

“Keep a diary,” she advised. “We can determine if there’s a link.”

Thus was my pedagogic legacy shattered in an instant. I’ve spent decades advising students not to tell patients they have a bad case of anything and never to ask them to keep diaries. Then, a foremost medical writer in a leading cultural journal endorses the reverse of both lessons. What was I thinking all these years?

I counseled students not to call any case “bad” because I saw how patients took it personally if I told them that. No matter how mild their diagnosis – rosacea and seborrhea, maladies less emperors than footmen– patients who heard theirs called “bad” looked sad, even insulted. Sad and insulted patients may give up and don’t follow treatment advice. (With such a bad case, why bother?) I didn’t urge patients to think that way. I just couldn’t ignore that they did. By contrast, assuring people that their case “wasn’t bad at all!” made them light up like Halloween pumpkins.

As for diaries, I’ve filed a few that patients handed me over the years. I showed these detailed chronicles to students to illustrate the lengths to which people will go to explain the unexplainable, like the ups and downs of idiopathic urticaria, eczema, and so forth:
 

• Thursday, August 6th, had sushi at a restaurant with friends.
• Sunday, September 3rd, watched science-fiction movie, unable to sleep that night.
• Monday, October 2nd, discarded fourth new detergent.

And so on.

In the meantime, several times each working day patients would troop in with randomly reoccurring conditions, atopic dermatitis above all, prompting dialogues like these:

“This is crazy! I never had anything like this before!”

“Well, actually, Ms. Jones, I treated you for the same thing in 2006.”

*********************

“This is bizarre! I never had this, and no one in my family ever did either.”

“I see. Well, here’s a prescription.”

“Come to think of it, my Mom had sensitive skin, and I get these dry patches on my arms and legs every winter.”

********************

“I’ve changed my soap three times and thrown out my makeup four times, and the rash keeps coming back. What should I do?”

“Stop throwing out your soap and makeup?”

And so on and on.

Sometimes, of course, semi-plausible causes seem to surface, such as stress. The question is, How useful is it to point this out? Consider the New Yorker case. Once the doctor “determined there is a link,” how might the conversation go?

“We have found the trigger, Mr. Smith. It’s stress.”

“Great! What should I do?”

“Don’t get laid off.”

No doctor (I hope) would ever say that, but patients present reports like the following all the time:

“As a kid, I was allergic to milk, but I’m not anymore.” (No, he wasn’t – he had infantile eczema that got blamed on milk.)

“Penicillin gave me hives.” (But, the hives lasted 6 weeks after the penicillin was stopped, which showed that the hives were idiopathic.)

“I’m very sensitive. I can’t use any moisturizer, any makeup, or all pills.” (People generate long litanies of sensitivities, piling one spurious correlation on another.)

Who benefits from “determining the link” when there isn’t any? Not the patients I’ve been seeing for forty years. Your patients? Maybe detergent manufacturers?

As to my errant pedagogy, with any luck, my students don’t remember a word I told them, a safe assumption for any teacher.

Either that or they don’t read the New Yorker.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@frontlinemedcom.com.