Atopic Dermatitis

The increasing use of methylisothiazolinone by itself in cosmetic and toiletry products has earned the preservative the title of contact allergen of the year from the American Contact Dermatitis Society.

Methylisothiazolinone (MI), a moderate-strong sensitizer, is important to know about, because a few years ago it was introduced into the market as a stand-alone preservative at up to 100 parts per million, Dr. Donald V. Belsito, professor of clinical dermatology at Columbia University, N.Y., said at the society’s annual meeting.

Previously, MI was used only in combination with methylchloroisothiazolinone (MCI), and the concentration limit of MI in that combination was 3.75 ppm for rinse-off products, and 1.8 ppm for leave-on products. Even at those lower limits, the MCI/MI combination in 2009-2010 was considered the fifth most common cause of preservative allergy.

The new 100-ppm limit (instituted based on the belief that MI was a weaker sensitizer than MCI) represents a 25-fold increase in the permitted concentration in cosmetics, Dr. Belsito noted.

At least one study, however, has shown that the eliciting concentration for MI reactivity can be as low as 5 ppm, Dr. Mari Paz Castanedo-Tardana of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and Dr. Kathryn A. Zug of Geisel School of Medicine at Dartmouth, Hanover, N.H., noted in an article in the January/February issue of Dermatitis, which granted MI its dubious 2013 title.

Dr. Castanedo-Tardana and Dr. Zug noted that in 2010, data suggested that more than 2,400 U.S. cosmetic products contained MI, which represents a doubling since 2007. The preservative is also used in industrial products without limit, thus providing other opportunities for exposure, such as occupational exposure (Dermatitis 2013;24:1-6).

An important problem is that few data exist concerning the cross-reaction patterns of MCI and MI, the authors noted.

"Bruze et al. showed that a small proportion of patch test subjects sensitized to MCI/MI also reacted to MI. Isaksson et al. also suggested that patients with high patch test reactivity to MCI may also react to high concentrations of MI (1,000 ppm). The percentage of concomitant reactions between MCI/MI and MI in the patch test population is relevant with regard to the diagnosis of MI contact allergy," according to the authors. They also noted that in a Danish study, a Finnish study, and a German study, only 40%, 66%, and 67% of patients with a positive reaction to MI, respectively, also had a positive reaction to MCI/MI.

The limited experience with MI-only patch tests concentrations also helped the allergen gain its newly bestowed title.

Concentrations of 300 ppm (0.03% aq), 500 ppm (0.05% aq), 1,000 ppm (0.1% aq), and 2,000 ppm (0.2% aq) have been tested, and all have yielded relatively similar percentages of positive test reactions.

"As with any other allergen, the ideal patch test concentration should be able to detect as many cases of contact allergy as possible without causing irritant reactions or active sensitization," the authors said, noting that preliminary results from Denmark suggest that 2,000 ppm (0.2% aq) is an appropriate concentration.

For now, however, it is likely that since MI is not routinely tested in any standard screening series, allergy to this preservative is being widely overlooked.

In fact, reports from Europe show that the frequency of allergy to MI is already at the same level as other preservatives that have been available for many years.

"Methylisothiazolinone should be considered as a potential suspect allergen among patients with suspected cosmetic dermatitis, facial dermatitis, and sunscreen allergy," the authors said, concluding that the addition of MI to an allergen screening series "will likely uncover otherwise undiagnosed cases of preservative contact allergy."

The presenter and authors reported having no disclosures.

[email protected]

The increasing use of methylisothiazolinone by itself in cosmetic and toiletry products has earned the preservative the title of contact allergen of the year from the American Contact Dermatitis Society.

Methylisothiazolinone (MI), a moderate-strong sensitizer, is important to know about, because a few years ago it was introduced into the market as a stand-alone preservative at up to 100 parts per million, Dr. Donald V. Belsito, professor of clinical dermatology at Columbia University, N.Y., said at the society’s annual meeting.

Previously, MI was used only in combination with methylchloroisothiazolinone (MCI), and the concentration limit of MI in that combination was 3.75 ppm for rinse-off products, and 1.8 ppm for leave-on products. Even at those lower limits, the MCI/MI combination in 2009-2010 was considered the fifth most common cause of preservative allergy.

The new 100-ppm limit (instituted based on the belief that MI was a weaker sensitizer than MCI) represents a 25-fold increase in the permitted concentration in cosmetics, Dr. Belsito noted.

At least one study, however, has shown that the eliciting concentration for MI reactivity can be as low as 5 ppm, Dr. Mari Paz Castanedo-Tardana of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and Dr. Kathryn A. Zug of Geisel School of Medicine at Dartmouth, Hanover, N.H., noted in an article in the January/February issue of Dermatitis, which granted MI its dubious 2013 title.

Dr. Castanedo-Tardana and Dr. Zug noted that in 2010, data suggested that more than 2,400 U.S. cosmetic products contained MI, which represents a doubling since 2007. The preservative is also used in industrial products without limit, thus providing other opportunities for exposure, such as occupational exposure (Dermatitis 2013;24:1-6).

An important problem is that few data exist concerning the cross-reaction patterns of MCI and MI, the authors noted.

"Bruze et al. showed that a small proportion of patch test subjects sensitized to MCI/MI also reacted to MI. Isaksson et al. also suggested that patients with high patch test reactivity to MCI may also react to high concentrations of MI (1,000 ppm). The percentage of concomitant reactions between MCI/MI and MI in the patch test population is relevant with regard to the diagnosis of MI contact allergy," according to the authors. They also noted that in a Danish study, a Finnish study, and a German study, only 40%, 66%, and 67% of patients with a positive reaction to MI, respectively, also had a positive reaction to MCI/MI.

The limited experience with MI-only patch tests concentrations also helped the allergen gain its newly bestowed title.

Concentrations of 300 ppm (0.03% aq), 500 ppm (0.05% aq), 1,000 ppm (0.1% aq), and 2,000 ppm (0.2% aq) have been tested, and all have yielded relatively similar percentages of positive test reactions.

"As with any other allergen, the ideal patch test concentration should be able to detect as many cases of contact allergy as possible without causing irritant reactions or active sensitization," the authors said, noting that preliminary results from Denmark suggest that 2,000 ppm (0.2% aq) is an appropriate concentration.

For now, however, it is likely that since MI is not routinely tested in any standard screening series, allergy to this preservative is being widely overlooked.

In fact, reports from Europe show that the frequency of allergy to MI is already at the same level as other preservatives that have been available for many years.

"Methylisothiazolinone should be considered as a potential suspect allergen among patients with suspected cosmetic dermatitis, facial dermatitis, and sunscreen allergy," the authors said, concluding that the addition of MI to an allergen screening series "will likely uncover otherwise undiagnosed cases of preservative contact allergy."

The presenter and authors reported having no disclosures.

[email protected]

The increasing use of methylisothiazolinone by itself in cosmetic and toiletry products has earned the preservative the title of contact allergen of the year from the American Contact Dermatitis Society.

Methylisothiazolinone (MI), a moderate-strong sensitizer, is important to know about, because a few years ago it was introduced into the market as a stand-alone preservative at up to 100 parts per million, Dr. Donald V. Belsito, professor of clinical dermatology at Columbia University, N.Y., said at the society’s annual meeting.

Previously, MI was used only in combination with methylchloroisothiazolinone (MCI), and the concentration limit of MI in that combination was 3.75 ppm for rinse-off products, and 1.8 ppm for leave-on products. Even at those lower limits, the MCI/MI combination in 2009-2010 was considered the fifth most common cause of preservative allergy.

The new 100-ppm limit (instituted based on the belief that MI was a weaker sensitizer than MCI) represents a 25-fold increase in the permitted concentration in cosmetics, Dr. Belsito noted.

At least one study, however, has shown that the eliciting concentration for MI reactivity can be as low as 5 ppm, Dr. Mari Paz Castanedo-Tardana of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and Dr. Kathryn A. Zug of Geisel School of Medicine at Dartmouth, Hanover, N.H., noted in an article in the January/February issue of Dermatitis, which granted MI its dubious 2013 title.

Dr. Castanedo-Tardana and Dr. Zug noted that in 2010, data suggested that more than 2,400 U.S. cosmetic products contained MI, which represents a doubling since 2007. The preservative is also used in industrial products without limit, thus providing other opportunities for exposure, such as occupational exposure (Dermatitis 2013;24:1-6).

An important problem is that few data exist concerning the cross-reaction patterns of MCI and MI, the authors noted.

"Bruze et al. showed that a small proportion of patch test subjects sensitized to MCI/MI also reacted to MI. Isaksson et al. also suggested that patients with high patch test reactivity to MCI may also react to high concentrations of MI (1,000 ppm). The percentage of concomitant reactions between MCI/MI and MI in the patch test population is relevant with regard to the diagnosis of MI contact allergy," according to the authors. They also noted that in a Danish study, a Finnish study, and a German study, only 40%, 66%, and 67% of patients with a positive reaction to MI, respectively, also had a positive reaction to MCI/MI.

The limited experience with MI-only patch tests concentrations also helped the allergen gain its newly bestowed title.

Concentrations of 300 ppm (0.03% aq), 500 ppm (0.05% aq), 1,000 ppm (0.1% aq), and 2,000 ppm (0.2% aq) have been tested, and all have yielded relatively similar percentages of positive test reactions.

"As with any other allergen, the ideal patch test concentration should be able to detect as many cases of contact allergy as possible without causing irritant reactions or active sensitization," the authors said, noting that preliminary results from Denmark suggest that 2,000 ppm (0.2% aq) is an appropriate concentration.

For now, however, it is likely that since MI is not routinely tested in any standard screening series, allergy to this preservative is being widely overlooked.

In fact, reports from Europe show that the frequency of allergy to MI is already at the same level as other preservatives that have been available for many years.

"Methylisothiazolinone should be considered as a potential suspect allergen among patients with suspected cosmetic dermatitis, facial dermatitis, and sunscreen allergy," the authors said, concluding that the addition of MI to an allergen screening series "will likely uncover otherwise undiagnosed cases of preservative contact allergy."

The presenter and authors reported having no disclosures.

[email protected]

SAN ANTONIO – Omalizumab diminished the signs and symptoms of chronic idiopathic urticaria in a dose-dependent fashion in a phase III study of 323 patients who failed to respond adequately to H1-antihistamines.

After 12 weeks of treatment with the recombinant humanized monoclonal antibody, improvements from baseline in weekly itch-severity scores were significantly greater in patients randomized to receive three doses of either 300 mg or 150 mg every 4 weeks, compared with placebo (score change of -9.8 and -8.1 vs. -5.1, respectively). The itch-severity score in patients randomized to receive a 75-mg dose changed by -5.9 points, but this did not differ significantly from the change in the placebo group, according to Dr. Marcus Maurer of Charite-Universitatsmedizin, Berlin. The report was published online on Feb. 24 in the New England Journal of Medicine.

The findings from this international double-blind trial were reported simultaneously at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In addition to meeting the primary 12-week response endpoint of change in weekly itch-severity score, patients receiving the 300-mg and 150-mg doses of omalizumab also experienced significant improvements, compared with patients given placebo, on all but one secondary endpoint, including change in the 7-day urticaria activity score (UAS7), change in the score for the weekly number of hives, time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less, the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, and change from baseline in the overall score on the Dermatology Life Quality Index. Those receiving 300 mg, but not those receiving 150 mg, also experienced significant improvement in the proportion of angioedema-free days from weeks 4-12 (N. Engl. J. Med. 2013 Feb. 24 [doi:10.1056/NEJMoa1215372]).

In a post hoc analysis at 12 weeks, 53%, 23%, 18%, and 10%, of those in the 300-mg, 150-mg, 75-mg, and placebo groups, respectively, were completely free of hives, and 44%, 22%, 16%, and 5%, respectively, were free of both hives and itching.

Of note, many patients experienced extremely rapid improvement, raising questions about a potential, as-yet unidentified and fundamental characteristic of this disease, study coauthors Dr. Thomas B. Casale, professor of medicine and medical microbiology and immunology and chief of allergy/immunology at Creighton University Medical Center, Omaha, Neb., and Dr. Allen P. Kaplan, clinical professor of medicine at the Medical University of South Carolina, Charleston, reported during a press briefing at AAAAI.

They explained that omalizumab, currently approved as an add-on therapy for moderate to severe persistent allergic asthma, is known to bind the allergic antibody immunoglobulin E (IgE). Many patients with chronic urticaria have an antibody that binds to a protein on the surface of histamine-containing cells, and that protein binds IgE.

"Just one injection drops one’s IgE level pretty close to zero ... and we learned that when we drop IgE to rock bottom, the protein on the cell to which it is attached also drops – and that’s the protein that the circulating antibody interacts with. The thinking was that if we drop the surface protein low enough, there’s nothing for the antibody to react with, and the hives would improve," he said.

This was, in fact, the case, as demonstrated in a phase I study of 12 patients, in which 7 patients responded dramatically, 4 responded partially, and 1 had no response. These findings led to the current phase III study, which is one of three such studies that investigators hope will lead to the drug’s approval for chronic idiopathic urticaria, because the high cost of the drug is prohibitive with respect to off-label use.

The same effect was seen in the current study.

This effect, however, takes a couple weeks to become apparent, so the rapid responses that occur in numerous patients suggest there is something more at play.

"This is working even faster than we thought, and probably there is a function of the allergic antibody that we do not yet understand," Dr. Kaplan said. "So this is going to be not only a terrific therapy for the disorder, but will lead to research in the future that probably – we hope – will elucidate the underlying abnormality of chronic urticaria beyond our current understanding of it. It’s very exciting, because it might elucidate some fundamental analogy that we don’t appreciate, and would have implications for allergic disease across the board."

The current study comprised patients aged 12-75 years who had a 6-month or longer history of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks at any time prior to enrollment (despite H1-antihistamine use), a UAS7 of 16 or more during a 7-day period, a weekly itch-severity score of at least 8, a score of at least 4 on the UAS on at least one of the screening-visit days, and receipt of a licensed dose of a second-generation H1-antihistamine for at least 3 consecutive days immediately prior to the screening visit. Those with a clearly defined underlying cause for their symptoms were excluded. The doses evaluated in this study were based on a prior dose-ranging study, which showed no additional benefit with doses over 300 mg, the investigators said.

Patients continued to receive stable doses of H1-antihistamines throughout the 12-week treatment period, and were permitted to use diphenhydramine as a rescue medication.

Omalizumab was well tolerated in this study, with a similar number of adverse events occurring across the treatment groups. Serious adverse events occurred more often in the 300-mg group, with 6% of patients in that group experiencing a serious adverse event, compared with 3% of patients in the placebo group, and 1% of patients in the 150-mg and 75-mg groups, but the events were not considered to be related to the study drug.

The duration of response, however, was limited, as noted during a 16-week observation period following the initial 12-week treatment period.

Although the weekly itch-severity scores did not return to baseline during follow-up, they did increase to the levels seen in the placebo group.

The findings are nonetheless encouraging, Dr. Kaplan said, noting that this disease, which can have dramatic adverse effects on quality of life, is not uncommon, and can be difficult to treat, with about half of all patients failing to respond to standard therapy with high dose antihistamines. Alternate treatments used to treat the disease, including steroids and cyclosporine, can be effective, but can be highly toxic, he said.

"For refractory patients we have nothing that matches (omalizumab’s) combination of this kind of efficacy with low side effects, so many of us in the field kind of view this as a game changer for the patients," he said.

This study was sponsored by Genentech and Novartis Pharma. Several study authors made disclosures. A complete list of these disclosures is available with the full text of the article at NEJM.org.

[email protected]

SAN ANTONIO – Omalizumab diminished the signs and symptoms of chronic idiopathic urticaria in a dose-dependent fashion in a phase III study of 323 patients who failed to respond adequately to H1-antihistamines.

After 12 weeks of treatment with the recombinant humanized monoclonal antibody, improvements from baseline in weekly itch-severity scores were significantly greater in patients randomized to receive three doses of either 300 mg or 150 mg every 4 weeks, compared with placebo (score change of -9.8 and -8.1 vs. -5.1, respectively). The itch-severity score in patients randomized to receive a 75-mg dose changed by -5.9 points, but this did not differ significantly from the change in the placebo group, according to Dr. Marcus Maurer of Charite-Universitatsmedizin, Berlin. The report was published online on Feb. 24 in the New England Journal of Medicine.

The findings from this international double-blind trial were reported simultaneously at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In addition to meeting the primary 12-week response endpoint of change in weekly itch-severity score, patients receiving the 300-mg and 150-mg doses of omalizumab also experienced significant improvements, compared with patients given placebo, on all but one secondary endpoint, including change in the 7-day urticaria activity score (UAS7), change in the score for the weekly number of hives, time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less, the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, and change from baseline in the overall score on the Dermatology Life Quality Index. Those receiving 300 mg, but not those receiving 150 mg, also experienced significant improvement in the proportion of angioedema-free days from weeks 4-12 (N. Engl. J. Med. 2013 Feb. 24 [doi:10.1056/NEJMoa1215372]).

In a post hoc analysis at 12 weeks, 53%, 23%, 18%, and 10%, of those in the 300-mg, 150-mg, 75-mg, and placebo groups, respectively, were completely free of hives, and 44%, 22%, 16%, and 5%, respectively, were free of both hives and itching.

Of note, many patients experienced extremely rapid improvement, raising questions about a potential, as-yet unidentified and fundamental characteristic of this disease, study coauthors Dr. Thomas B. Casale, professor of medicine and medical microbiology and immunology and chief of allergy/immunology at Creighton University Medical Center, Omaha, Neb., and Dr. Allen P. Kaplan, clinical professor of medicine at the Medical University of South Carolina, Charleston, reported during a press briefing at AAAAI.

They explained that omalizumab, currently approved as an add-on therapy for moderate to severe persistent allergic asthma, is known to bind the allergic antibody immunoglobulin E (IgE). Many patients with chronic urticaria have an antibody that binds to a protein on the surface of histamine-containing cells, and that protein binds IgE.

"Just one injection drops one’s IgE level pretty close to zero ... and we learned that when we drop IgE to rock bottom, the protein on the cell to which it is attached also drops – and that’s the protein that the circulating antibody interacts with. The thinking was that if we drop the surface protein low enough, there’s nothing for the antibody to react with, and the hives would improve," he said.

This was, in fact, the case, as demonstrated in a phase I study of 12 patients, in which 7 patients responded dramatically, 4 responded partially, and 1 had no response. These findings led to the current phase III study, which is one of three such studies that investigators hope will lead to the drug’s approval for chronic idiopathic urticaria, because the high cost of the drug is prohibitive with respect to off-label use.

The same effect was seen in the current study.

This effect, however, takes a couple weeks to become apparent, so the rapid responses that occur in numerous patients suggest there is something more at play.

"This is working even faster than we thought, and probably there is a function of the allergic antibody that we do not yet understand," Dr. Kaplan said. "So this is going to be not only a terrific therapy for the disorder, but will lead to research in the future that probably – we hope – will elucidate the underlying abnormality of chronic urticaria beyond our current understanding of it. It’s very exciting, because it might elucidate some fundamental analogy that we don’t appreciate, and would have implications for allergic disease across the board."

The current study comprised patients aged 12-75 years who had a 6-month or longer history of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks at any time prior to enrollment (despite H1-antihistamine use), a UAS7 of 16 or more during a 7-day period, a weekly itch-severity score of at least 8, a score of at least 4 on the UAS on at least one of the screening-visit days, and receipt of a licensed dose of a second-generation H1-antihistamine for at least 3 consecutive days immediately prior to the screening visit. Those with a clearly defined underlying cause for their symptoms were excluded. The doses evaluated in this study were based on a prior dose-ranging study, which showed no additional benefit with doses over 300 mg, the investigators said.

Patients continued to receive stable doses of H1-antihistamines throughout the 12-week treatment period, and were permitted to use diphenhydramine as a rescue medication.

Omalizumab was well tolerated in this study, with a similar number of adverse events occurring across the treatment groups. Serious adverse events occurred more often in the 300-mg group, with 6% of patients in that group experiencing a serious adverse event, compared with 3% of patients in the placebo group, and 1% of patients in the 150-mg and 75-mg groups, but the events were not considered to be related to the study drug.

The duration of response, however, was limited, as noted during a 16-week observation period following the initial 12-week treatment period.

Although the weekly itch-severity scores did not return to baseline during follow-up, they did increase to the levels seen in the placebo group.

The findings are nonetheless encouraging, Dr. Kaplan said, noting that this disease, which can have dramatic adverse effects on quality of life, is not uncommon, and can be difficult to treat, with about half of all patients failing to respond to standard therapy with high dose antihistamines. Alternate treatments used to treat the disease, including steroids and cyclosporine, can be effective, but can be highly toxic, he said.

"For refractory patients we have nothing that matches (omalizumab’s) combination of this kind of efficacy with low side effects, so many of us in the field kind of view this as a game changer for the patients," he said.

This study was sponsored by Genentech and Novartis Pharma. Several study authors made disclosures. A complete list of these disclosures is available with the full text of the article at NEJM.org.

[email protected]

SAN ANTONIO – Omalizumab diminished the signs and symptoms of chronic idiopathic urticaria in a dose-dependent fashion in a phase III study of 323 patients who failed to respond adequately to H1-antihistamines.

After 12 weeks of treatment with the recombinant humanized monoclonal antibody, improvements from baseline in weekly itch-severity scores were significantly greater in patients randomized to receive three doses of either 300 mg or 150 mg every 4 weeks, compared with placebo (score change of -9.8 and -8.1 vs. -5.1, respectively). The itch-severity score in patients randomized to receive a 75-mg dose changed by -5.9 points, but this did not differ significantly from the change in the placebo group, according to Dr. Marcus Maurer of Charite-Universitatsmedizin, Berlin. The report was published online on Feb. 24 in the New England Journal of Medicine.

The findings from this international double-blind trial were reported simultaneously at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In addition to meeting the primary 12-week response endpoint of change in weekly itch-severity score, patients receiving the 300-mg and 150-mg doses of omalizumab also experienced significant improvements, compared with patients given placebo, on all but one secondary endpoint, including change in the 7-day urticaria activity score (UAS7), change in the score for the weekly number of hives, time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less, the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, and change from baseline in the overall score on the Dermatology Life Quality Index. Those receiving 300 mg, but not those receiving 150 mg, also experienced significant improvement in the proportion of angioedema-free days from weeks 4-12 (N. Engl. J. Med. 2013 Feb. 24 [doi:10.1056/NEJMoa1215372]).

In a post hoc analysis at 12 weeks, 53%, 23%, 18%, and 10%, of those in the 300-mg, 150-mg, 75-mg, and placebo groups, respectively, were completely free of hives, and 44%, 22%, 16%, and 5%, respectively, were free of both hives and itching.

Of note, many patients experienced extremely rapid improvement, raising questions about a potential, as-yet unidentified and fundamental characteristic of this disease, study coauthors Dr. Thomas B. Casale, professor of medicine and medical microbiology and immunology and chief of allergy/immunology at Creighton University Medical Center, Omaha, Neb., and Dr. Allen P. Kaplan, clinical professor of medicine at the Medical University of South Carolina, Charleston, reported during a press briefing at AAAAI.

They explained that omalizumab, currently approved as an add-on therapy for moderate to severe persistent allergic asthma, is known to bind the allergic antibody immunoglobulin E (IgE). Many patients with chronic urticaria have an antibody that binds to a protein on the surface of histamine-containing cells, and that protein binds IgE.

"Just one injection drops one’s IgE level pretty close to zero ... and we learned that when we drop IgE to rock bottom, the protein on the cell to which it is attached also drops – and that’s the protein that the circulating antibody interacts with. The thinking was that if we drop the surface protein low enough, there’s nothing for the antibody to react with, and the hives would improve," he said.

This was, in fact, the case, as demonstrated in a phase I study of 12 patients, in which 7 patients responded dramatically, 4 responded partially, and 1 had no response. These findings led to the current phase III study, which is one of three such studies that investigators hope will lead to the drug’s approval for chronic idiopathic urticaria, because the high cost of the drug is prohibitive with respect to off-label use.

The same effect was seen in the current study.

This effect, however, takes a couple weeks to become apparent, so the rapid responses that occur in numerous patients suggest there is something more at play.

"This is working even faster than we thought, and probably there is a function of the allergic antibody that we do not yet understand," Dr. Kaplan said. "So this is going to be not only a terrific therapy for the disorder, but will lead to research in the future that probably – we hope – will elucidate the underlying abnormality of chronic urticaria beyond our current understanding of it. It’s very exciting, because it might elucidate some fundamental analogy that we don’t appreciate, and would have implications for allergic disease across the board."

The current study comprised patients aged 12-75 years who had a 6-month or longer history of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks at any time prior to enrollment (despite H1-antihistamine use), a UAS7 of 16 or more during a 7-day period, a weekly itch-severity score of at least 8, a score of at least 4 on the UAS on at least one of the screening-visit days, and receipt of a licensed dose of a second-generation H1-antihistamine for at least 3 consecutive days immediately prior to the screening visit. Those with a clearly defined underlying cause for their symptoms were excluded. The doses evaluated in this study were based on a prior dose-ranging study, which showed no additional benefit with doses over 300 mg, the investigators said.

Patients continued to receive stable doses of H1-antihistamines throughout the 12-week treatment period, and were permitted to use diphenhydramine as a rescue medication.

Omalizumab was well tolerated in this study, with a similar number of adverse events occurring across the treatment groups. Serious adverse events occurred more often in the 300-mg group, with 6% of patients in that group experiencing a serious adverse event, compared with 3% of patients in the placebo group, and 1% of patients in the 150-mg and 75-mg groups, but the events were not considered to be related to the study drug.

The duration of response, however, was limited, as noted during a 16-week observation period following the initial 12-week treatment period.

Although the weekly itch-severity scores did not return to baseline during follow-up, they did increase to the levels seen in the placebo group.

The findings are nonetheless encouraging, Dr. Kaplan said, noting that this disease, which can have dramatic adverse effects on quality of life, is not uncommon, and can be difficult to treat, with about half of all patients failing to respond to standard therapy with high dose antihistamines. Alternate treatments used to treat the disease, including steroids and cyclosporine, can be effective, but can be highly toxic, he said.

"For refractory patients we have nothing that matches (omalizumab’s) combination of this kind of efficacy with low side effects, so many of us in the field kind of view this as a game changer for the patients," he said.

This study was sponsored by Genentech and Novartis Pharma. Several study authors made disclosures. A complete list of these disclosures is available with the full text of the article at NEJM.org.

[email protected]

Recent studies have suggested a link between atopic dermatitis and particular neurobehavioral abnormalities. Dr. Lawrence F. Eichenfield of the University of California, San Diego, discusses the evolving perspective on the relationship between atopic dermatitis and attention deficit hyperactivity disorder (ADHD) in children.

Recent studies have suggested a link between atopic dermatitis and particular neurobehavioral abnormalities. Dr. Lawrence F. Eichenfield of the University of California, San Diego, discusses the evolving perspective on the relationship between atopic dermatitis and attention deficit hyperactivity disorder (ADHD) in children.

Recent studies have suggested a link between atopic dermatitis and particular neurobehavioral abnormalities. Dr. Lawrence F. Eichenfield of the University of California, San Diego, discusses the evolving perspective on the relationship between atopic dermatitis and attention deficit hyperactivity disorder (ADHD) in children.

PRAGUE – Reliance upon the time-honored tools for diagnosis of contact allergy due to fragrances will cause physicians to miss many cases, Dr. David E. Cohen said at the annual congress of the European Academy of Dermatology and Venereology.

"The old fragrance mix – fragrance mix I – and the use of balsam of Peru as fragrance screening tools really won’t capture contact dermatitis involving allergens to more modern fragrances," cautioned Dr. Cohen, professor and vice chair of the department of dermatology at New York University.

"I remember my grandmother always smelling like rosewater and naphthalene – like mothballs and rosewater. But we don’t smell like that anymore. Now we tend to use more botanical extracts. We see tea tree oil and jasmine appearing in our personal care products, and if we don’t test for those more contemporary fragrances, we will miss a very important source of contact dermatitis," he continued.

That’s why fragrance mix II (FM II) was developed. FM II has been incorporated into the North American Contact Dermatitis Group’s standard screening tray. It is not, however, part of the widely used T.R.U.E. (Thin-Layer Rapid Use Epicutaneous) test, nor is it included in the European standard screening series.

Multiple studies have documented that a substantial proportion of patients with allergic contact dermatitis will react only to the newer fragrances, and not to FM I or balsam of Peru. For example, a multicenter Hungarian study published earlier this year found that of 565 patients patch tested because of skin symptoms provoked by scented products, 17% exhibited contact hypersensitivity to one or more components of FM II. Moreover, 48% of FM II–positive patients reacted only to FM II, not FM I, balsam of Peru, or other test materials (Dermatitis 2012;23:71-4).

Similarly, a Mayo Clinic study of 945 patients patch tested using both the standard screening tray with FM II and the T.R.U.E. test found that 49% of patients reacted to one or more preservatives and 31% reacted to at least one fragrance or botanical additive. However, the T.R.U.E. test didn’t capture 23% of patients with a preservative allergy and 11% of those with a fragrance or botanical allergy (J. Am. Acad. Dermatol. 2010;63:789-98).

Fragrances pose one of the greatest challenges in the field of contact dermatitis. That’s because there are roughly 3,000 fragrance chemicals utilized in personal care products and cosmetics, and at least 100 of them have been described as causing contact dermatitis in patients. It can be difficult to assess the clinical relevance of positive patch test reactions because physicians don’t know what’s contained in North American fragrances. The fragrance industry is lucrative, secretive, and self-regulated.

Fragrance allergy is on the rise in children and adolescents, probably because they are being exposed to an onslaught of fragrance chemicals at a younger and younger age.

"When I grew up there was a bar of soap in the shower and, if we were lucky, shampoo; and if there was no shampoo we used the bar of soap. I have 19- and 17-year-old daughters, and if you go into their bathroom there are four different shampoos and three conditioners. There are things with glitter in there, and moisturizers and cosmetics, most of which I don’t even know what they’re for. All of them are fragrances. Folks are starting their exposure when they’re 7 and 8 years old. That was never the case before," said Dr. Cohen, who is also director of occupational, environmental, and allergic dermatology at the university.

The commercially available six-ingredient FM II panel is a 14% concentration composed of citronellol 0.5%, hydroxyisohexyl 3-cyclohexenecarboxyaldehyde (Lyral) 2.5%, hexyl cinnamal 5.0%, citral 1.0%, coumarin 2.5%, and farnesol 2.5%.

A long-standing point of contention has been the question of whether patients with atopic disease are more likely than nonatopic individuals to experience contact sensitivity, or less. The latest evidence suggests patients with asthma or severe atopic dermatitis have an overall lower prevalence of contact sensitization compared with nonatopic controls, with one striking exception.

In this very large study conducted by investigators at the Danish National Allergy Research Center, Copenhagen, an inverse association was found between atopic disease and contact allergy to metals and all groups of chemicals ... except fragrances. The prevalence of contact sensitization to fragrances was significantly higher in patients with atopic dermatitis than in controls. The investigators recommended that patients with atopic dermatitis be instructed to avoid scented moisturizers (Allergy 2012;67:1157-64).

The Danes found that patients with severe atopic dermatitis were 30% less likely than controls to be patch test–positive for contact sensitivity overall, whereas mild to moderate atopic dermatitis did not suppress contact sensitization. Again, fragrances constituted the exception: Not only did patients with severe atopic dermatitis have an increased prevalence of contact sensitization to fragrance chemicals, those with mild or moderate atopic dermatitis did, too, Dr. Cohen noted.

He reported having no financial conflicts.

[email protected]

PRAGUE – Reliance upon the time-honored tools for diagnosis of contact allergy due to fragrances will cause physicians to miss many cases, Dr. David E. Cohen said at the annual congress of the European Academy of Dermatology and Venereology.

"The old fragrance mix – fragrance mix I – and the use of balsam of Peru as fragrance screening tools really won’t capture contact dermatitis involving allergens to more modern fragrances," cautioned Dr. Cohen, professor and vice chair of the department of dermatology at New York University.

"I remember my grandmother always smelling like rosewater and naphthalene – like mothballs and rosewater. But we don’t smell like that anymore. Now we tend to use more botanical extracts. We see tea tree oil and jasmine appearing in our personal care products, and if we don’t test for those more contemporary fragrances, we will miss a very important source of contact dermatitis," he continued.

That’s why fragrance mix II (FM II) was developed. FM II has been incorporated into the North American Contact Dermatitis Group’s standard screening tray. It is not, however, part of the widely used T.R.U.E. (Thin-Layer Rapid Use Epicutaneous) test, nor is it included in the European standard screening series.

Multiple studies have documented that a substantial proportion of patients with allergic contact dermatitis will react only to the newer fragrances, and not to FM I or balsam of Peru. For example, a multicenter Hungarian study published earlier this year found that of 565 patients patch tested because of skin symptoms provoked by scented products, 17% exhibited contact hypersensitivity to one or more components of FM II. Moreover, 48% of FM II–positive patients reacted only to FM II, not FM I, balsam of Peru, or other test materials (Dermatitis 2012;23:71-4).

Similarly, a Mayo Clinic study of 945 patients patch tested using both the standard screening tray with FM II and the T.R.U.E. test found that 49% of patients reacted to one or more preservatives and 31% reacted to at least one fragrance or botanical additive. However, the T.R.U.E. test didn’t capture 23% of patients with a preservative allergy and 11% of those with a fragrance or botanical allergy (J. Am. Acad. Dermatol. 2010;63:789-98).

Fragrances pose one of the greatest challenges in the field of contact dermatitis. That’s because there are roughly 3,000 fragrance chemicals utilized in personal care products and cosmetics, and at least 100 of them have been described as causing contact dermatitis in patients. It can be difficult to assess the clinical relevance of positive patch test reactions because physicians don’t know what’s contained in North American fragrances. The fragrance industry is lucrative, secretive, and self-regulated.

Fragrance allergy is on the rise in children and adolescents, probably because they are being exposed to an onslaught of fragrance chemicals at a younger and younger age.

"When I grew up there was a bar of soap in the shower and, if we were lucky, shampoo; and if there was no shampoo we used the bar of soap. I have 19- and 17-year-old daughters, and if you go into their bathroom there are four different shampoos and three conditioners. There are things with glitter in there, and moisturizers and cosmetics, most of which I don’t even know what they’re for. All of them are fragrances. Folks are starting their exposure when they’re 7 and 8 years old. That was never the case before," said Dr. Cohen, who is also director of occupational, environmental, and allergic dermatology at the university.

The commercially available six-ingredient FM II panel is a 14% concentration composed of citronellol 0.5%, hydroxyisohexyl 3-cyclohexenecarboxyaldehyde (Lyral) 2.5%, hexyl cinnamal 5.0%, citral 1.0%, coumarin 2.5%, and farnesol 2.5%.

A long-standing point of contention has been the question of whether patients with atopic disease are more likely than nonatopic individuals to experience contact sensitivity, or less. The latest evidence suggests patients with asthma or severe atopic dermatitis have an overall lower prevalence of contact sensitization compared with nonatopic controls, with one striking exception.

In this very large study conducted by investigators at the Danish National Allergy Research Center, Copenhagen, an inverse association was found between atopic disease and contact allergy to metals and all groups of chemicals ... except fragrances. The prevalence of contact sensitization to fragrances was significantly higher in patients with atopic dermatitis than in controls. The investigators recommended that patients with atopic dermatitis be instructed to avoid scented moisturizers (Allergy 2012;67:1157-64).

The Danes found that patients with severe atopic dermatitis were 30% less likely than controls to be patch test–positive for contact sensitivity overall, whereas mild to moderate atopic dermatitis did not suppress contact sensitization. Again, fragrances constituted the exception: Not only did patients with severe atopic dermatitis have an increased prevalence of contact sensitization to fragrance chemicals, those with mild or moderate atopic dermatitis did, too, Dr. Cohen noted.

He reported having no financial conflicts.

[email protected]

PRAGUE – Reliance upon the time-honored tools for diagnosis of contact allergy due to fragrances will cause physicians to miss many cases, Dr. David E. Cohen said at the annual congress of the European Academy of Dermatology and Venereology.

"The old fragrance mix – fragrance mix I – and the use of balsam of Peru as fragrance screening tools really won’t capture contact dermatitis involving allergens to more modern fragrances," cautioned Dr. Cohen, professor and vice chair of the department of dermatology at New York University.

"I remember my grandmother always smelling like rosewater and naphthalene – like mothballs and rosewater. But we don’t smell like that anymore. Now we tend to use more botanical extracts. We see tea tree oil and jasmine appearing in our personal care products, and if we don’t test for those more contemporary fragrances, we will miss a very important source of contact dermatitis," he continued.

That’s why fragrance mix II (FM II) was developed. FM II has been incorporated into the North American Contact Dermatitis Group’s standard screening tray. It is not, however, part of the widely used T.R.U.E. (Thin-Layer Rapid Use Epicutaneous) test, nor is it included in the European standard screening series.

Multiple studies have documented that a substantial proportion of patients with allergic contact dermatitis will react only to the newer fragrances, and not to FM I or balsam of Peru. For example, a multicenter Hungarian study published earlier this year found that of 565 patients patch tested because of skin symptoms provoked by scented products, 17% exhibited contact hypersensitivity to one or more components of FM II. Moreover, 48% of FM II–positive patients reacted only to FM II, not FM I, balsam of Peru, or other test materials (Dermatitis 2012;23:71-4).

Similarly, a Mayo Clinic study of 945 patients patch tested using both the standard screening tray with FM II and the T.R.U.E. test found that 49% of patients reacted to one or more preservatives and 31% reacted to at least one fragrance or botanical additive. However, the T.R.U.E. test didn’t capture 23% of patients with a preservative allergy and 11% of those with a fragrance or botanical allergy (J. Am. Acad. Dermatol. 2010;63:789-98).

Fragrances pose one of the greatest challenges in the field of contact dermatitis. That’s because there are roughly 3,000 fragrance chemicals utilized in personal care products and cosmetics, and at least 100 of them have been described as causing contact dermatitis in patients. It can be difficult to assess the clinical relevance of positive patch test reactions because physicians don’t know what’s contained in North American fragrances. The fragrance industry is lucrative, secretive, and self-regulated.

Fragrance allergy is on the rise in children and adolescents, probably because they are being exposed to an onslaught of fragrance chemicals at a younger and younger age.

"When I grew up there was a bar of soap in the shower and, if we were lucky, shampoo; and if there was no shampoo we used the bar of soap. I have 19- and 17-year-old daughters, and if you go into their bathroom there are four different shampoos and three conditioners. There are things with glitter in there, and moisturizers and cosmetics, most of which I don’t even know what they’re for. All of them are fragrances. Folks are starting their exposure when they’re 7 and 8 years old. That was never the case before," said Dr. Cohen, who is also director of occupational, environmental, and allergic dermatology at the university.

The commercially available six-ingredient FM II panel is a 14% concentration composed of citronellol 0.5%, hydroxyisohexyl 3-cyclohexenecarboxyaldehyde (Lyral) 2.5%, hexyl cinnamal 5.0%, citral 1.0%, coumarin 2.5%, and farnesol 2.5%.

A long-standing point of contention has been the question of whether patients with atopic disease are more likely than nonatopic individuals to experience contact sensitivity, or less. The latest evidence suggests patients with asthma or severe atopic dermatitis have an overall lower prevalence of contact sensitization compared with nonatopic controls, with one striking exception.

In this very large study conducted by investigators at the Danish National Allergy Research Center, Copenhagen, an inverse association was found between atopic disease and contact allergy to metals and all groups of chemicals ... except fragrances. The prevalence of contact sensitization to fragrances was significantly higher in patients with atopic dermatitis than in controls. The investigators recommended that patients with atopic dermatitis be instructed to avoid scented moisturizers (Allergy 2012;67:1157-64).

The Danes found that patients with severe atopic dermatitis were 30% less likely than controls to be patch test–positive for contact sensitivity overall, whereas mild to moderate atopic dermatitis did not suppress contact sensitization. Again, fragrances constituted the exception: Not only did patients with severe atopic dermatitis have an increased prevalence of contact sensitization to fragrance chemicals, those with mild or moderate atopic dermatitis did, too, Dr. Cohen noted.

He reported having no financial conflicts.

[email protected]

PRAGUE – Tacrolimus 0.03% ointment has earned first-line, treatment-of-choice status in atopic blepharoconjunctivitis, the most common ocular complication of atopic dermatitis, Dr. Ville Kiiski said at the annual congress of the European Academy of Dermatology and Venereology.

In a 10-year, single-center review of 338 patients on long-term topical therapy for atopic blepharoconjunctivitis with either tacrolimus (Protopic), pimecrolimus 1% cream (Elidel), or topical corticosteroids, tacrolimus displayed the best efficacy and tolerability, according to Dr. Kiiski of Helsinki University Central Hospital.

Tacrolimus ointment was the primary therapy in 297 patients as young as 2 years old. Thirty-three patients were on pimecrolimus, while just eight patients were treated mainly with topical steroids. Most Finnish physicians are reluctant to prescribe topical steroids for long-term use in the eyelid area because of the well-known associated increased risks of cataracts, elevated intraocular pressure, and skin atrophy, the dermatologist noted.

The mean follow-up was 1.5 years for treatment efficacy and 5.8 years for malignancy risk.

The treatment discontinuation rate because of intolerance of side effects was 33% with pimecrolimus and 9.1% for tacrolimus. Twenty-two percent of patients placed on pimecrolimus discontinued the drug because of insufficient efficacy, compared with 1.6% on tacrolimus.

The blepharitis response rate was 90% in tacrolimus-treated patients, 79% with pimecrolimus, and 88% in the handful of patients on topical steroids. The conjunctivitis response rates were 80%, 55%, and 50% with tacrolimus, pimecrolimus, and topical steroids, respectively.

Tacrolimus-treated patients were an adjusted 2.37-fold more likely to experience significant improvement in their blepharitis than patients on pimecrolimus and 2.34-fold more likely to see improvement in their conjunctivitis.

Intraocular pressure dropped over time by a mean of 0.6 mm Hg in patients on either of the topical calcineurin inhibitors. None of the three topical therapies was associated with adverse effects on vision, lens, or cornea, nor were there adverse trends in terms of bacterial infections or malignancies.

Atopic blepharoconjunctivitis occurs when inflammatory disease activity at the eyelid margins traumatizes the ocular surface, aggravating keratitis and conjunctivitis.

The study was free of commercial sponsorship or investigator financial conflicts.

PRAGUE – Tacrolimus 0.03% ointment has earned first-line, treatment-of-choice status in atopic blepharoconjunctivitis, the most common ocular complication of atopic dermatitis, Dr. Ville Kiiski said at the annual congress of the European Academy of Dermatology and Venereology.

In a 10-year, single-center review of 338 patients on long-term topical therapy for atopic blepharoconjunctivitis with either tacrolimus (Protopic), pimecrolimus 1% cream (Elidel), or topical corticosteroids, tacrolimus displayed the best efficacy and tolerability, according to Dr. Kiiski of Helsinki University Central Hospital.

Tacrolimus ointment was the primary therapy in 297 patients as young as 2 years old. Thirty-three patients were on pimecrolimus, while just eight patients were treated mainly with topical steroids. Most Finnish physicians are reluctant to prescribe topical steroids for long-term use in the eyelid area because of the well-known associated increased risks of cataracts, elevated intraocular pressure, and skin atrophy, the dermatologist noted.

The mean follow-up was 1.5 years for treatment efficacy and 5.8 years for malignancy risk.

The treatment discontinuation rate because of intolerance of side effects was 33% with pimecrolimus and 9.1% for tacrolimus. Twenty-two percent of patients placed on pimecrolimus discontinued the drug because of insufficient efficacy, compared with 1.6% on tacrolimus.

The blepharitis response rate was 90% in tacrolimus-treated patients, 79% with pimecrolimus, and 88% in the handful of patients on topical steroids. The conjunctivitis response rates were 80%, 55%, and 50% with tacrolimus, pimecrolimus, and topical steroids, respectively.

Tacrolimus-treated patients were an adjusted 2.37-fold more likely to experience significant improvement in their blepharitis than patients on pimecrolimus and 2.34-fold more likely to see improvement in their conjunctivitis.

Intraocular pressure dropped over time by a mean of 0.6 mm Hg in patients on either of the topical calcineurin inhibitors. None of the three topical therapies was associated with adverse effects on vision, lens, or cornea, nor were there adverse trends in terms of bacterial infections or malignancies.

Atopic blepharoconjunctivitis occurs when inflammatory disease activity at the eyelid margins traumatizes the ocular surface, aggravating keratitis and conjunctivitis.

The study was free of commercial sponsorship or investigator financial conflicts.

PRAGUE – Tacrolimus 0.03% ointment has earned first-line, treatment-of-choice status in atopic blepharoconjunctivitis, the most common ocular complication of atopic dermatitis, Dr. Ville Kiiski said at the annual congress of the European Academy of Dermatology and Venereology.

In a 10-year, single-center review of 338 patients on long-term topical therapy for atopic blepharoconjunctivitis with either tacrolimus (Protopic), pimecrolimus 1% cream (Elidel), or topical corticosteroids, tacrolimus displayed the best efficacy and tolerability, according to Dr. Kiiski of Helsinki University Central Hospital.

Tacrolimus ointment was the primary therapy in 297 patients as young as 2 years old. Thirty-three patients were on pimecrolimus, while just eight patients were treated mainly with topical steroids. Most Finnish physicians are reluctant to prescribe topical steroids for long-term use in the eyelid area because of the well-known associated increased risks of cataracts, elevated intraocular pressure, and skin atrophy, the dermatologist noted.

The mean follow-up was 1.5 years for treatment efficacy and 5.8 years for malignancy risk.

The treatment discontinuation rate because of intolerance of side effects was 33% with pimecrolimus and 9.1% for tacrolimus. Twenty-two percent of patients placed on pimecrolimus discontinued the drug because of insufficient efficacy, compared with 1.6% on tacrolimus.

The blepharitis response rate was 90% in tacrolimus-treated patients, 79% with pimecrolimus, and 88% in the handful of patients on topical steroids. The conjunctivitis response rates were 80%, 55%, and 50% with tacrolimus, pimecrolimus, and topical steroids, respectively.

Tacrolimus-treated patients were an adjusted 2.37-fold more likely to experience significant improvement in their blepharitis than patients on pimecrolimus and 2.34-fold more likely to see improvement in their conjunctivitis.

Intraocular pressure dropped over time by a mean of 0.6 mm Hg in patients on either of the topical calcineurin inhibitors. None of the three topical therapies was associated with adverse effects on vision, lens, or cornea, nor were there adverse trends in terms of bacterial infections or malignancies.

Atopic blepharoconjunctivitis occurs when inflammatory disease activity at the eyelid margins traumatizes the ocular surface, aggravating keratitis and conjunctivitis.

The study was free of commercial sponsorship or investigator financial conflicts.

Patients often ask their dermatologists for recommendations on over-the-counter moisturizers, said Dr. Joshua Zeichner.

The trouble is that "many dermatologists don’t really know what makes a good moisturizer, and are unfamiliar with the latest advances in moisturizing technology," he said at SDEF Las Vegas Dermatology Seminar.

While the purpose of all moisturizers is simple enough – to boost and maintain the water content of the skin – their formulations and the manner of their activity vary widely. Some work by increasing the expression of aquaporins, the water channels in the skin cell membrane; others by replacing skin lipids, temporarily repairing the skin’s barrier function and improving appearance.

Any high-quality moisturizer will contain a mixture of humectant, emollient, and occlusive ingredients, said Dr. Zeichner, director of cosmetic and clinical research in dermatology at Mount Sinai Medical Center in New York.

Among the novel humectants being incorporated into moisturizers today are natural moisturizing factors (NMF), an umbrella term for the naturally occurring humectants glycerol, urea, and lactic acid, along with the amino acids urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), which are produced by the breakdown of filaggrin.

Many moisturizers contain ceramides, the major lipids that make up the "mortar" between skin-cell "bricks" in the stratum corneum; moisturizers also may contain ceramide precursors.

"Applying a moisturizer with [the ceramide precursor] pseudoceramide 5 has been shown to lead to an increase in ceramide levels in the stratum corneum," Dr. Zeichner said. "However, it’s unclear whether the ingredient is directly incorporated into those ceramides. Regardless, you can see the clinical improvement."

Generally with all moisturizers, he said, "we need more studies to evaluate the long-term effects to the skin beyond just the immediate effect."

Glyceryl glucoside, a modified glycerin molecule that enhances the activity of aquaporin channels, shows promise as a humectant, Dr. Zeichner said.

He described glyceryl glucoside as a "super humectant" whose effect on skin may last longer than that of other humectants.

Dr. Zeichner also tipped his hat to an old school moisturizer ingredient – colloidal oatmeal.

"There’s a lot of talk about all of these exciting new technologies but you don’t want to forget about tried and true colloidal oatmeal," he said. Oatmeal, which has occlusive, humectant, and emollient properties, "serves as the backbone for many skin brands and works very well. Advances in cosmetic chemistry have made oatmeal formulations much more elegant now – they’re not your grandmother’s oatmeal anymore."

Dr. Zeichner disclosed financial relationships with Allergan, Bayer, Beiersdorf, Galderma, Johnson and Johnson, L’Oreal, Medicis, Onset, Pharmaderm, Procter and Gamble, and Valeant.

SDEF and this news organization are owned by Frontline Medical Communications.

Patients often ask their dermatologists for recommendations on over-the-counter moisturizers, said Dr. Joshua Zeichner.

The trouble is that "many dermatologists don’t really know what makes a good moisturizer, and are unfamiliar with the latest advances in moisturizing technology," he said at SDEF Las Vegas Dermatology Seminar.

While the purpose of all moisturizers is simple enough – to boost and maintain the water content of the skin – their formulations and the manner of their activity vary widely. Some work by increasing the expression of aquaporins, the water channels in the skin cell membrane; others by replacing skin lipids, temporarily repairing the skin’s barrier function and improving appearance.

Any high-quality moisturizer will contain a mixture of humectant, emollient, and occlusive ingredients, said Dr. Zeichner, director of cosmetic and clinical research in dermatology at Mount Sinai Medical Center in New York.

Among the novel humectants being incorporated into moisturizers today are natural moisturizing factors (NMF), an umbrella term for the naturally occurring humectants glycerol, urea, and lactic acid, along with the amino acids urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), which are produced by the breakdown of filaggrin.

Many moisturizers contain ceramides, the major lipids that make up the "mortar" between skin-cell "bricks" in the stratum corneum; moisturizers also may contain ceramide precursors.

"Applying a moisturizer with [the ceramide precursor] pseudoceramide 5 has been shown to lead to an increase in ceramide levels in the stratum corneum," Dr. Zeichner said. "However, it’s unclear whether the ingredient is directly incorporated into those ceramides. Regardless, you can see the clinical improvement."

Generally with all moisturizers, he said, "we need more studies to evaluate the long-term effects to the skin beyond just the immediate effect."

Glyceryl glucoside, a modified glycerin molecule that enhances the activity of aquaporin channels, shows promise as a humectant, Dr. Zeichner said.

He described glyceryl glucoside as a "super humectant" whose effect on skin may last longer than that of other humectants.

Dr. Zeichner also tipped his hat to an old school moisturizer ingredient – colloidal oatmeal.

"There’s a lot of talk about all of these exciting new technologies but you don’t want to forget about tried and true colloidal oatmeal," he said. Oatmeal, which has occlusive, humectant, and emollient properties, "serves as the backbone for many skin brands and works very well. Advances in cosmetic chemistry have made oatmeal formulations much more elegant now – they’re not your grandmother’s oatmeal anymore."

Dr. Zeichner disclosed financial relationships with Allergan, Bayer, Beiersdorf, Galderma, Johnson and Johnson, L’Oreal, Medicis, Onset, Pharmaderm, Procter and Gamble, and Valeant.

SDEF and this news organization are owned by Frontline Medical Communications.

Patients often ask their dermatologists for recommendations on over-the-counter moisturizers, said Dr. Joshua Zeichner.

The trouble is that "many dermatologists don’t really know what makes a good moisturizer, and are unfamiliar with the latest advances in moisturizing technology," he said at SDEF Las Vegas Dermatology Seminar.

While the purpose of all moisturizers is simple enough – to boost and maintain the water content of the skin – their formulations and the manner of their activity vary widely. Some work by increasing the expression of aquaporins, the water channels in the skin cell membrane; others by replacing skin lipids, temporarily repairing the skin’s barrier function and improving appearance.

Any high-quality moisturizer will contain a mixture of humectant, emollient, and occlusive ingredients, said Dr. Zeichner, director of cosmetic and clinical research in dermatology at Mount Sinai Medical Center in New York.

Among the novel humectants being incorporated into moisturizers today are natural moisturizing factors (NMF), an umbrella term for the naturally occurring humectants glycerol, urea, and lactic acid, along with the amino acids urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), which are produced by the breakdown of filaggrin.

Many moisturizers contain ceramides, the major lipids that make up the "mortar" between skin-cell "bricks" in the stratum corneum; moisturizers also may contain ceramide precursors.

"Applying a moisturizer with [the ceramide precursor] pseudoceramide 5 has been shown to lead to an increase in ceramide levels in the stratum corneum," Dr. Zeichner said. "However, it’s unclear whether the ingredient is directly incorporated into those ceramides. Regardless, you can see the clinical improvement."

Generally with all moisturizers, he said, "we need more studies to evaluate the long-term effects to the skin beyond just the immediate effect."

Glyceryl glucoside, a modified glycerin molecule that enhances the activity of aquaporin channels, shows promise as a humectant, Dr. Zeichner said.

He described glyceryl glucoside as a "super humectant" whose effect on skin may last longer than that of other humectants.

Dr. Zeichner also tipped his hat to an old school moisturizer ingredient – colloidal oatmeal.

"There’s a lot of talk about all of these exciting new technologies but you don’t want to forget about tried and true colloidal oatmeal," he said. Oatmeal, which has occlusive, humectant, and emollient properties, "serves as the backbone for many skin brands and works very well. Advances in cosmetic chemistry have made oatmeal formulations much more elegant now – they’re not your grandmother’s oatmeal anymore."

Dr. Zeichner disclosed financial relationships with Allergan, Bayer, Beiersdorf, Galderma, Johnson and Johnson, L’Oreal, Medicis, Onset, Pharmaderm, Procter and Gamble, and Valeant.

SDEF and this news organization are owned by Frontline Medical Communications.

RALEIGH, N.C. – Atopic dermatitis is a disease that until now has gone underappreciated by regulatory authorities, the pharmaceutical industry, and the general public, according to thought leaders determined to turn the situation around.

"The first and probably foremost reason atopic dermatitis has been somewhat ignored is that it is perceived as a childhood disease, and that makes development of drugs very, very difficult. First, you have to go through studies in adults and then you have to go through children," Dr. Lisa A. Beck noted during a special plenary session devoted to atopic dermatitis at the conference.

Courtesy Mrs. Emily Boynton, URMC Public Relations Department

Another stumbling block is that researchers haven’t adequately documented the negative effects atopic dermatitis can have on daily life for patients and caregivers. Clinicians who care for atopy patients are aware of it. The outside world is not, observed Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.). Also, better diagnostic criteria for atopic dermatitis are needed. The diagnosis isn’t always as straightforward as in psoriasis, which is "the great comparator in our range of diseases," she said.

A damaging perception that’s particularly entrenched within the regulatory agencies is that atopic dermatitis is not high priority because it lacks serious comorbidities, Dr. Beck continued.

Research Barriers

"That’s something we come up against in atopic dermatitis all the time: the idea that it’s a disease of misery rather than a disease of mortality," agreed Dr. Neil Graham of Regeneron Pharmaceuticals in Tarrytown, N.Y. "However, our view is that human misery is something we should be trying to treat therapeutically, and that this has value both economically and to society. I think we’ve seen this accomplished successfully with psoriasis, which is the template we can use in atopic dermatitis."

Biopharmaceutical companies are interested in applying the psoriasis drug development template to atopic dermatitis. Regeneron is developing a biologic agent that simultaneously blocks interleukins-4 and -13 for the treatment of atopic dermatitis and other diseases whose predominant mechanism involves Th2-driven eosinophilic inflammation, including eosinophilic asthma, chronic sinusitis with nasal polyps, and conjunctival allergic disease. The company wants an agent that can be subcutaneously injected every week or two, noted Dr. Graham.

"We hope eventually to intervene in children and potentially interrupt the atopic march. It will probably take us many years to get there," he said.

Regulatory agencies will almost certainly require that clinical trials involving any biologic agent under development for atopic dermatitis initially be restricted to patients with moderate to severe disease.

That’s a problem, according to Dr. Graham, because the Food and Drug Administration defines the clinical severity of atopic dermatitis using the Investigator’s Global Assessment (IGA) scale: a limited tool that’s not up to the task of capturing the full impact of the disease. Better means of defining the moderate to severely affected patient subset are essential. Also, a standardized, clinically relevant measure of disease severity reduction in response to treatment is needed – something akin to the Psoriasis Area Severity Index (PASI) 50 or -75 as used in psoriasis.

Dr. Eric Simpson agreed that regulatory authorities haven’t devoted sufficient attention to study design requirements or definitions of therapeutic success. For instance, the FDA requires evidence of improvement in the IGA as the bar that must be cleared in order to obtain approval of drugs for atopic dermatitis. Yet the IGA has never been adequately validated, nor has the metric’s definition been standardized. Indeed, the definition changes over time, from one phase-III clinical trial to the next.

"The inter-relater reliability of the IGA is unknown. I think it could be a major issue," said Dr. Simpson of the Oregon Health and Science University, Portland.

He proposed that participants in the SID special session on atopic dermatitis create a position paper recommending better outcome measures to the FDA. "We need to work with the agency to do what’s best for good clinical research," he said.

Identifying Biomarkers

According to Dr. Graham, atopic dermatitis is on the radar of major biotech companies that have biologic agents for psoriasis. They are working to develop biologics for atopic dermatitis, targeting a variety of pathways including interleukins-5, -4, and -13, as well as IgE.

Reliable biomarkers are needed to make drug development in atopic dermatitis go quickly and efficiently. After all, biomarker data are now routinely incorporated into early-phase development of new drugs for psoriasis, and these data are included in support of new drug applications to the FDA. But objective biomarkers have been notably lacking in atopic dermatitis, he noted.

Dr. Emma Guttman-Yassky announced help is at hand. While efforts to identify blood biomarkers have proved deeply disappointing, skin biomarkers are another story. She and her coinvestigators have identified a set of reliable skin biomarkers of therapeutic response in atopic dermatitis patients.

"We believe that these biomarkers represent the molecular fingerprints of the disease and might be key to future development of targeted treatments," said Dr. Guttman-Yassky, director of occupational and contact dermatitis at Mount Sinai Medical Center, New York.

She and her coinvestigators took lesional and nonlesional skin biopsies from 12 atopic dermatitis patients before and after undergoing narrow-band UVB phototherapy three times weekly for 12 weeks, a regimen the patients responded to with a mean 81% reduction in SCORAD index scores. Reversal of epidermal hyperplasia and abnormal keratinocyte differentiation – the histologic hallmarks of atopic dermatitis – was associated with elimination of inflammatory leukocytes and Th2-associated cytokines and chemokines (J. Allergy Clin. Immunol. 2011;128:583-93).

Among the skin biomarkers of atopic dermatitis that reversed with effective therapy were inflammatory dendritic epidermal cells, myeloid and plasmacytoid dendritic cells, CD3+ T cells, and interleukins-4 and -13.

This study, as well as another by Dr. Guttman-Yassky and her colleagues (in press), demonstrated a major role for interleukin-22 in atopic dermatitis. The cytokine was markedly overexpressed in lesional skin, with resultant upregulation of the antimicrobial protein’s S100A7, S100A8, and S100A9. After narrow-band UVB therapy, expression of IL-22 expression was downregulated, as were the IL-22-induced chemokines S100A7-9.

Expression of the three antimicrobial proteins in lesional skin also appears to be useful as a biomarker defining acute disease. Their levels jump within 3 days after onset of acute atopic dermatitis, according to Dr. Guttman-Yassky.

"Are we there yet in terms of biomarkers in atopic dermatitis? That’s the million-dollar question. Regarding biomarker availability, I think yes. We now have biomarkers that are highly informative on the reversal of disease pathology with treatment," she said. "I believe that the next step is clinical trials with specific immune antagonists that incorporate biomarkers of response. I think biomarkers are key if we want to know if new therapies really work. This will enhance early decisions and reduce the cost of developing new treatments."

An important implication of the narrow-band UVB/biomarker study in terms of atopic dermatitis pathogenesis is that the data argue against a fixed genetic phenotype, since the atopic dermatitis epidermal phenotype was shown to be reversed with broad-based immune-targeted phototherapy. Instead, the study results argue in favor of what Dr. Guttman-Yassky called "the inside-out hypothesis" of atopic dermatitis, which postulates that the epidermal abnormalities that define the disease are caused by underlying immune activation.

Her studies were supported by the National Institutes of Health.

HOME Project Seeks Standardization

During the same session, Dr. Hywel C. Williams provided an update on a major international project called Harmonising Outcome Measures for Eczema (HOME). The goal of the HOME project is to develop a consensus on a core set of outcome measures to be used in all atopic dermatitis clinical research. This should make future studies easier to compare, contrast, and synthesize in meta-analyses.

A minimum set of core outcome measures in atopic dermatitis is needed because the situation can be chaotic, noted Dr. Williams, professor of dermatology and director of the Center for Evidence-Based Dermatology at the University of Nottingham (U.K.).

"There are more than 20 named scales for atopic dermatitis, including SCORAD, POEM, SASSAD, ADASI, ADAM, EASI, and the FSSS. Some have been only partly tested. Many have not been tested at all. At international meetings I see people shouting at each other, trying to communicate what the results of their studies mean. Some people are in the SCORAD camp, some are in the SASSAD camp, others are in the EASI camp. How can we possibly communicate? This is a shameful situation which we really have to put right if we are to progress," he said.

The HOME project is modeled after Outcome Measures in Rheumatology, or OMERACT, an international consensus group that meets every 2 years with the goal of raising the quality of rheumatologic research. HOME comprises atopic dermatitis researchers, clinical experts, journal editors, patient advocates, and representatives from the European regulatory agency. The FDA was invited but didn’t attend last year’s HOME meeting in Amsterdam, where working groups were formed to identify the best evidence-based instruments for assessing atopic disease signs, symptoms, flares, quality of life, and treatment efficacy and safety. The HOME group will meet next year in San Diego on April 6-7.

Aside from Dr. Graham, a Regeneron employee, the other speakers in the special session reported receiving research grants from various sources but declared having no conflicts of interest with regard to their presentations.

RALEIGH, N.C. – Atopic dermatitis is a disease that until now has gone underappreciated by regulatory authorities, the pharmaceutical industry, and the general public, according to thought leaders determined to turn the situation around.

"The first and probably foremost reason atopic dermatitis has been somewhat ignored is that it is perceived as a childhood disease, and that makes development of drugs very, very difficult. First, you have to go through studies in adults and then you have to go through children," Dr. Lisa A. Beck noted during a special plenary session devoted to atopic dermatitis at the conference.

Courtesy Mrs. Emily Boynton, URMC Public Relations Department

Another stumbling block is that researchers haven’t adequately documented the negative effects atopic dermatitis can have on daily life for patients and caregivers. Clinicians who care for atopy patients are aware of it. The outside world is not, observed Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.). Also, better diagnostic criteria for atopic dermatitis are needed. The diagnosis isn’t always as straightforward as in psoriasis, which is "the great comparator in our range of diseases," she said.

A damaging perception that’s particularly entrenched within the regulatory agencies is that atopic dermatitis is not high priority because it lacks serious comorbidities, Dr. Beck continued.

Research Barriers

"That’s something we come up against in atopic dermatitis all the time: the idea that it’s a disease of misery rather than a disease of mortality," agreed Dr. Neil Graham of Regeneron Pharmaceuticals in Tarrytown, N.Y. "However, our view is that human misery is something we should be trying to treat therapeutically, and that this has value both economically and to society. I think we’ve seen this accomplished successfully with psoriasis, which is the template we can use in atopic dermatitis."

Biopharmaceutical companies are interested in applying the psoriasis drug development template to atopic dermatitis. Regeneron is developing a biologic agent that simultaneously blocks interleukins-4 and -13 for the treatment of atopic dermatitis and other diseases whose predominant mechanism involves Th2-driven eosinophilic inflammation, including eosinophilic asthma, chronic sinusitis with nasal polyps, and conjunctival allergic disease. The company wants an agent that can be subcutaneously injected every week or two, noted Dr. Graham.

"We hope eventually to intervene in children and potentially interrupt the atopic march. It will probably take us many years to get there," he said.

Regulatory agencies will almost certainly require that clinical trials involving any biologic agent under development for atopic dermatitis initially be restricted to patients with moderate to severe disease.

That’s a problem, according to Dr. Graham, because the Food and Drug Administration defines the clinical severity of atopic dermatitis using the Investigator’s Global Assessment (IGA) scale: a limited tool that’s not up to the task of capturing the full impact of the disease. Better means of defining the moderate to severely affected patient subset are essential. Also, a standardized, clinically relevant measure of disease severity reduction in response to treatment is needed – something akin to the Psoriasis Area Severity Index (PASI) 50 or -75 as used in psoriasis.

Dr. Eric Simpson agreed that regulatory authorities haven’t devoted sufficient attention to study design requirements or definitions of therapeutic success. For instance, the FDA requires evidence of improvement in the IGA as the bar that must be cleared in order to obtain approval of drugs for atopic dermatitis. Yet the IGA has never been adequately validated, nor has the metric’s definition been standardized. Indeed, the definition changes over time, from one phase-III clinical trial to the next.

"The inter-relater reliability of the IGA is unknown. I think it could be a major issue," said Dr. Simpson of the Oregon Health and Science University, Portland.

He proposed that participants in the SID special session on atopic dermatitis create a position paper recommending better outcome measures to the FDA. "We need to work with the agency to do what’s best for good clinical research," he said.

Identifying Biomarkers

According to Dr. Graham, atopic dermatitis is on the radar of major biotech companies that have biologic agents for psoriasis. They are working to develop biologics for atopic dermatitis, targeting a variety of pathways including interleukins-5, -4, and -13, as well as IgE.

Reliable biomarkers are needed to make drug development in atopic dermatitis go quickly and efficiently. After all, biomarker data are now routinely incorporated into early-phase development of new drugs for psoriasis, and these data are included in support of new drug applications to the FDA. But objective biomarkers have been notably lacking in atopic dermatitis, he noted.

Dr. Emma Guttman-Yassky announced help is at hand. While efforts to identify blood biomarkers have proved deeply disappointing, skin biomarkers are another story. She and her coinvestigators have identified a set of reliable skin biomarkers of therapeutic response in atopic dermatitis patients.

"We believe that these biomarkers represent the molecular fingerprints of the disease and might be key to future development of targeted treatments," said Dr. Guttman-Yassky, director of occupational and contact dermatitis at Mount Sinai Medical Center, New York.

She and her coinvestigators took lesional and nonlesional skin biopsies from 12 atopic dermatitis patients before and after undergoing narrow-band UVB phototherapy three times weekly for 12 weeks, a regimen the patients responded to with a mean 81% reduction in SCORAD index scores. Reversal of epidermal hyperplasia and abnormal keratinocyte differentiation – the histologic hallmarks of atopic dermatitis – was associated with elimination of inflammatory leukocytes and Th2-associated cytokines and chemokines (J. Allergy Clin. Immunol. 2011;128:583-93).

Among the skin biomarkers of atopic dermatitis that reversed with effective therapy were inflammatory dendritic epidermal cells, myeloid and plasmacytoid dendritic cells, CD3+ T cells, and interleukins-4 and -13.

This study, as well as another by Dr. Guttman-Yassky and her colleagues (in press), demonstrated a major role for interleukin-22 in atopic dermatitis. The cytokine was markedly overexpressed in lesional skin, with resultant upregulation of the antimicrobial protein’s S100A7, S100A8, and S100A9. After narrow-band UVB therapy, expression of IL-22 expression was downregulated, as were the IL-22-induced chemokines S100A7-9.

Expression of the three antimicrobial proteins in lesional skin also appears to be useful as a biomarker defining acute disease. Their levels jump within 3 days after onset of acute atopic dermatitis, according to Dr. Guttman-Yassky.

"Are we there yet in terms of biomarkers in atopic dermatitis? That’s the million-dollar question. Regarding biomarker availability, I think yes. We now have biomarkers that are highly informative on the reversal of disease pathology with treatment," she said. "I believe that the next step is clinical trials with specific immune antagonists that incorporate biomarkers of response. I think biomarkers are key if we want to know if new therapies really work. This will enhance early decisions and reduce the cost of developing new treatments."

An important implication of the narrow-band UVB/biomarker study in terms of atopic dermatitis pathogenesis is that the data argue against a fixed genetic phenotype, since the atopic dermatitis epidermal phenotype was shown to be reversed with broad-based immune-targeted phototherapy. Instead, the study results argue in favor of what Dr. Guttman-Yassky called "the inside-out hypothesis" of atopic dermatitis, which postulates that the epidermal abnormalities that define the disease are caused by underlying immune activation.

Her studies were supported by the National Institutes of Health.

HOME Project Seeks Standardization

During the same session, Dr. Hywel C. Williams provided an update on a major international project called Harmonising Outcome Measures for Eczema (HOME). The goal of the HOME project is to develop a consensus on a core set of outcome measures to be used in all atopic dermatitis clinical research. This should make future studies easier to compare, contrast, and synthesize in meta-analyses.

A minimum set of core outcome measures in atopic dermatitis is needed because the situation can be chaotic, noted Dr. Williams, professor of dermatology and director of the Center for Evidence-Based Dermatology at the University of Nottingham (U.K.).

"There are more than 20 named scales for atopic dermatitis, including SCORAD, POEM, SASSAD, ADASI, ADAM, EASI, and the FSSS. Some have been only partly tested. Many have not been tested at all. At international meetings I see people shouting at each other, trying to communicate what the results of their studies mean. Some people are in the SCORAD camp, some are in the SASSAD camp, others are in the EASI camp. How can we possibly communicate? This is a shameful situation which we really have to put right if we are to progress," he said.

The HOME project is modeled after Outcome Measures in Rheumatology, or OMERACT, an international consensus group that meets every 2 years with the goal of raising the quality of rheumatologic research. HOME comprises atopic dermatitis researchers, clinical experts, journal editors, patient advocates, and representatives from the European regulatory agency. The FDA was invited but didn’t attend last year’s HOME meeting in Amsterdam, where working groups were formed to identify the best evidence-based instruments for assessing atopic disease signs, symptoms, flares, quality of life, and treatment efficacy and safety. The HOME group will meet next year in San Diego on April 6-7.

Aside from Dr. Graham, a Regeneron employee, the other speakers in the special session reported receiving research grants from various sources but declared having no conflicts of interest with regard to their presentations.

RALEIGH, N.C. – Atopic dermatitis is a disease that until now has gone underappreciated by regulatory authorities, the pharmaceutical industry, and the general public, according to thought leaders determined to turn the situation around.

"The first and probably foremost reason atopic dermatitis has been somewhat ignored is that it is perceived as a childhood disease, and that makes development of drugs very, very difficult. First, you have to go through studies in adults and then you have to go through children," Dr. Lisa A. Beck noted during a special plenary session devoted to atopic dermatitis at the conference.

Courtesy Mrs. Emily Boynton, URMC Public Relations Department

Another stumbling block is that researchers haven’t adequately documented the negative effects atopic dermatitis can have on daily life for patients and caregivers. Clinicians who care for atopy patients are aware of it. The outside world is not, observed Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.). Also, better diagnostic criteria for atopic dermatitis are needed. The diagnosis isn’t always as straightforward as in psoriasis, which is "the great comparator in our range of diseases," she said.

A damaging perception that’s particularly entrenched within the regulatory agencies is that atopic dermatitis is not high priority because it lacks serious comorbidities, Dr. Beck continued.

Research Barriers

"That’s something we come up against in atopic dermatitis all the time: the idea that it’s a disease of misery rather than a disease of mortality," agreed Dr. Neil Graham of Regeneron Pharmaceuticals in Tarrytown, N.Y. "However, our view is that human misery is something we should be trying to treat therapeutically, and that this has value both economically and to society. I think we’ve seen this accomplished successfully with psoriasis, which is the template we can use in atopic dermatitis."

Biopharmaceutical companies are interested in applying the psoriasis drug development template to atopic dermatitis. Regeneron is developing a biologic agent that simultaneously blocks interleukins-4 and -13 for the treatment of atopic dermatitis and other diseases whose predominant mechanism involves Th2-driven eosinophilic inflammation, including eosinophilic asthma, chronic sinusitis with nasal polyps, and conjunctival allergic disease. The company wants an agent that can be subcutaneously injected every week or two, noted Dr. Graham.

"We hope eventually to intervene in children and potentially interrupt the atopic march. It will probably take us many years to get there," he said.

Regulatory agencies will almost certainly require that clinical trials involving any biologic agent under development for atopic dermatitis initially be restricted to patients with moderate to severe disease.

That’s a problem, according to Dr. Graham, because the Food and Drug Administration defines the clinical severity of atopic dermatitis using the Investigator’s Global Assessment (IGA) scale: a limited tool that’s not up to the task of capturing the full impact of the disease. Better means of defining the moderate to severely affected patient subset are essential. Also, a standardized, clinically relevant measure of disease severity reduction in response to treatment is needed – something akin to the Psoriasis Area Severity Index (PASI) 50 or -75 as used in psoriasis.

Dr. Eric Simpson agreed that regulatory authorities haven’t devoted sufficient attention to study design requirements or definitions of therapeutic success. For instance, the FDA requires evidence of improvement in the IGA as the bar that must be cleared in order to obtain approval of drugs for atopic dermatitis. Yet the IGA has never been adequately validated, nor has the metric’s definition been standardized. Indeed, the definition changes over time, from one phase-III clinical trial to the next.

"The inter-relater reliability of the IGA is unknown. I think it could be a major issue," said Dr. Simpson of the Oregon Health and Science University, Portland.

He proposed that participants in the SID special session on atopic dermatitis create a position paper recommending better outcome measures to the FDA. "We need to work with the agency to do what’s best for good clinical research," he said.

Identifying Biomarkers

According to Dr. Graham, atopic dermatitis is on the radar of major biotech companies that have biologic agents for psoriasis. They are working to develop biologics for atopic dermatitis, targeting a variety of pathways including interleukins-5, -4, and -13, as well as IgE.

Reliable biomarkers are needed to make drug development in atopic dermatitis go quickly and efficiently. After all, biomarker data are now routinely incorporated into early-phase development of new drugs for psoriasis, and these data are included in support of new drug applications to the FDA. But objective biomarkers have been notably lacking in atopic dermatitis, he noted.

Dr. Emma Guttman-Yassky announced help is at hand. While efforts to identify blood biomarkers have proved deeply disappointing, skin biomarkers are another story. She and her coinvestigators have identified a set of reliable skin biomarkers of therapeutic response in atopic dermatitis patients.

"We believe that these biomarkers represent the molecular fingerprints of the disease and might be key to future development of targeted treatments," said Dr. Guttman-Yassky, director of occupational and contact dermatitis at Mount Sinai Medical Center, New York.

She and her coinvestigators took lesional and nonlesional skin biopsies from 12 atopic dermatitis patients before and after undergoing narrow-band UVB phototherapy three times weekly for 12 weeks, a regimen the patients responded to with a mean 81% reduction in SCORAD index scores. Reversal of epidermal hyperplasia and abnormal keratinocyte differentiation – the histologic hallmarks of atopic dermatitis – was associated with elimination of inflammatory leukocytes and Th2-associated cytokines and chemokines (J. Allergy Clin. Immunol. 2011;128:583-93).

Among the skin biomarkers of atopic dermatitis that reversed with effective therapy were inflammatory dendritic epidermal cells, myeloid and plasmacytoid dendritic cells, CD3+ T cells, and interleukins-4 and -13.

This study, as well as another by Dr. Guttman-Yassky and her colleagues (in press), demonstrated a major role for interleukin-22 in atopic dermatitis. The cytokine was markedly overexpressed in lesional skin, with resultant upregulation of the antimicrobial protein’s S100A7, S100A8, and S100A9. After narrow-band UVB therapy, expression of IL-22 expression was downregulated, as were the IL-22-induced chemokines S100A7-9.

Expression of the three antimicrobial proteins in lesional skin also appears to be useful as a biomarker defining acute disease. Their levels jump within 3 days after onset of acute atopic dermatitis, according to Dr. Guttman-Yassky.

"Are we there yet in terms of biomarkers in atopic dermatitis? That’s the million-dollar question. Regarding biomarker availability, I think yes. We now have biomarkers that are highly informative on the reversal of disease pathology with treatment," she said. "I believe that the next step is clinical trials with specific immune antagonists that incorporate biomarkers of response. I think biomarkers are key if we want to know if new therapies really work. This will enhance early decisions and reduce the cost of developing new treatments."

An important implication of the narrow-band UVB/biomarker study in terms of atopic dermatitis pathogenesis is that the data argue against a fixed genetic phenotype, since the atopic dermatitis epidermal phenotype was shown to be reversed with broad-based immune-targeted phototherapy. Instead, the study results argue in favor of what Dr. Guttman-Yassky called "the inside-out hypothesis" of atopic dermatitis, which postulates that the epidermal abnormalities that define the disease are caused by underlying immune activation.

Her studies were supported by the National Institutes of Health.

HOME Project Seeks Standardization

During the same session, Dr. Hywel C. Williams provided an update on a major international project called Harmonising Outcome Measures for Eczema (HOME). The goal of the HOME project is to develop a consensus on a core set of outcome measures to be used in all atopic dermatitis clinical research. This should make future studies easier to compare, contrast, and synthesize in meta-analyses.

A minimum set of core outcome measures in atopic dermatitis is needed because the situation can be chaotic, noted Dr. Williams, professor of dermatology and director of the Center for Evidence-Based Dermatology at the University of Nottingham (U.K.).

"There are more than 20 named scales for atopic dermatitis, including SCORAD, POEM, SASSAD, ADASI, ADAM, EASI, and the FSSS. Some have been only partly tested. Many have not been tested at all. At international meetings I see people shouting at each other, trying to communicate what the results of their studies mean. Some people are in the SCORAD camp, some are in the SASSAD camp, others are in the EASI camp. How can we possibly communicate? This is a shameful situation which we really have to put right if we are to progress," he said.

The HOME project is modeled after Outcome Measures in Rheumatology, or OMERACT, an international consensus group that meets every 2 years with the goal of raising the quality of rheumatologic research. HOME comprises atopic dermatitis researchers, clinical experts, journal editors, patient advocates, and representatives from the European regulatory agency. The FDA was invited but didn’t attend last year’s HOME meeting in Amsterdam, where working groups were formed to identify the best evidence-based instruments for assessing atopic disease signs, symptoms, flares, quality of life, and treatment efficacy and safety. The HOME group will meet next year in San Diego on April 6-7.

Aside from Dr. Graham, a Regeneron employee, the other speakers in the special session reported receiving research grants from various sources but declared having no conflicts of interest with regard to their presentations.

In this month's program, Dr. Jeffrey Curtis discusses his study, which found new evidence supporting the safety of the shingles vaccine for patients on biologics.

Then, Dr. Jonathan Silverberg talks about the best climates for children with eczema.

Dr. Bruce Brod of the American Academy of Dermatology reports on which states have the toughest laws on indoor tanning, and he highlights the latest legislation on the matter.

Meanwhile, Dr. Lily Talakoub talks about a common summer skin condition, Pityrosporum folliculitis, and Dr. Alan Rockoff presents his musical marketing plan.

Don't miss another episode of The Skinny Podcast; subscribe for free on iTunes!

In this month's program, Dr. Jeffrey Curtis discusses his study, which found new evidence supporting the safety of the shingles vaccine for patients on biologics.

Then, Dr. Jonathan Silverberg talks about the best climates for children with eczema.

Dr. Bruce Brod of the American Academy of Dermatology reports on which states have the toughest laws on indoor tanning, and he highlights the latest legislation on the matter.

Meanwhile, Dr. Lily Talakoub talks about a common summer skin condition, Pityrosporum folliculitis, and Dr. Alan Rockoff presents his musical marketing plan.

Don't miss another episode of The Skinny Podcast; subscribe for free on iTunes!

In this month's program, Dr. Jeffrey Curtis discusses his study, which found new evidence supporting the safety of the shingles vaccine for patients on biologics.

Then, Dr. Jonathan Silverberg talks about the best climates for children with eczema.

Dr. Bruce Brod of the American Academy of Dermatology reports on which states have the toughest laws on indoor tanning, and he highlights the latest legislation on the matter.

Meanwhile, Dr. Lily Talakoub talks about a common summer skin condition, Pityrosporum folliculitis, and Dr. Alan Rockoff presents his musical marketing plan.

Don't miss another episode of The Skinny Podcast; subscribe for free on iTunes!

Oral immunotherapy using egg-white powder represents a highly promising therapeutic intervention for children with egg allergy, according to findings from a randomized, placebo-controlled trial reported online in the July 19 issue of the New England Journal of Medicine.

After 10 months of immunotherapy, none of the 15 children with egg allergy who received placebo as part of the double-blind study passed an oral food challenge of 5 g of egg-white powder, whereas 22 (55%) of 40 children who received oral immunotherapy passed the oral food challenge and were considered to be desensitized. At 22 months, 30 (75%) of the 40 children who received oral immunotherapy passed an oral food challenge with 10 g of egg-white powder, Dr. A. Wesley Burks, chair of the department of pediatrics at the University of North Carolina and chief physician of N.C. Children’s Hospital, his colleagues reported on behalf of the Consortium of Food Allergy Research.

Photo © paci77/iStockphoto.com

Of the 30 children who passed the oral food challenge at 22 months, 29 were rechallenged at 24 months with 10 g of egg-white powder, followed 1 hour later with one whole cooked egg (after having discontinued immunotherapy and egg consumption for 4-6 weeks); 11 (28%) passed the challenge and were considered to have "sustained unresponsiveness," the investigators reported (N. Engl. J. Med. 2012 July 19 [doi:10.1056/NEJMoa1200435]).

These 11 children then were instructed to add egg to their diet ad libitum. No adverse events were reported at the 30- and 36-month follow-ups.

Study participants were children aged 5-18 years (median, 7 years) with a convincing clinical history of egg allergy and a serum egg-specific IgE antibody level of more than 5 kU/L for those aged 6 years and older, and 12 kU/L or more for those aged 5 years. Those with a history of severe anaphylaxis after egg consumption were excluded.

The protocol for oral immunotherapy consisted of an initial-day dose escalation, a build-up phase, and a maintenance phase involving ingestion of up to 2 g of egg-white powder (equivalent of about one-third of an egg) daily.

Factors that were found to be associated with sustained unresponsiveness at 24 months were higher egg-specific IgG4 antibody levels at 10 months, smaller wheal diameter on skin-prick allergy testing at 22 months, and a decrease in wheal size from baseline to 22 months, the investigators noted.

Oral immunotherapy in this study was generally well tolerated, with adverse events occurring most frequently in association with oral-immunotherapy dosing. Most of the events were mild (grade 1), with only 1% being graded as moderate (grade 2). No severe adverse events occurred. Most events were oral or pharyngeal, and were associated with 25% of the 11,860 doses of oral immunotherapy, and with 3.9% of the 4,018 doses of placebo. The rate of symptoms decreased to 8.3% of 15,815 doses in the oral immunotherapy group after 10 months.

The findings could have important implications, given that the cumulative prevalence of egg allergy is approximately 2.6% by 2.5 years of age, and that egg avoidance (which is difficult and can adversely affect quality of life) is the only available treatment for egg allergy, investigators said.

However, for oral immunotherapy to be recommended as a standard of care, it is important to better define risks, compared with allergen avoidance; to determine the dosing regimens with the most favorable outcomes; to identify the patients most likely to benefit; and to develop postdesensitization strategies, the investigators concluded.

This study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health–National Center for Research Resources Clinical Translational Science Awards and Clinical Research Centers. Dr. A. Wesley Burks has been a consultant for companies including Dannon Co. Probiotic, McNeil Nutritionals, Merck, the Food Allergy & Anaphylaxis Network, and Novartis, and has grants or grants pending from the Food Allergy Initiative, the NIH, the National Peanut Board, and others. Some of his associates were consultants for companies including DBV Technologies, Allertein Therapeutics, and Sunovion, or received grants from various companies; other associates had no relevant financial disclosures.

CLARIFICATION 7/20/2012: The institutional affiliation of Dr. Burks has been updated to reflect his current position.

Oral immunotherapy using egg-white powder represents a highly promising therapeutic intervention for children with egg allergy, according to findings from a randomized, placebo-controlled trial reported online in the July 19 issue of the New England Journal of Medicine.

After 10 months of immunotherapy, none of the 15 children with egg allergy who received placebo as part of the double-blind study passed an oral food challenge of 5 g of egg-white powder, whereas 22 (55%) of 40 children who received oral immunotherapy passed the oral food challenge and were considered to be desensitized. At 22 months, 30 (75%) of the 40 children who received oral immunotherapy passed an oral food challenge with 10 g of egg-white powder, Dr. A. Wesley Burks, chair of the department of pediatrics at the University of North Carolina and chief physician of N.C. Children’s Hospital, his colleagues reported on behalf of the Consortium of Food Allergy Research.

Photo © paci77/iStockphoto.com

Of the 30 children who passed the oral food challenge at 22 months, 29 were rechallenged at 24 months with 10 g of egg-white powder, followed 1 hour later with one whole cooked egg (after having discontinued immunotherapy and egg consumption for 4-6 weeks); 11 (28%) passed the challenge and were considered to have "sustained unresponsiveness," the investigators reported (N. Engl. J. Med. 2012 July 19 [doi:10.1056/NEJMoa1200435]).

These 11 children then were instructed to add egg to their diet ad libitum. No adverse events were reported at the 30- and 36-month follow-ups.

Study participants were children aged 5-18 years (median, 7 years) with a convincing clinical history of egg allergy and a serum egg-specific IgE antibody level of more than 5 kU/L for those aged 6 years and older, and 12 kU/L or more for those aged 5 years. Those with a history of severe anaphylaxis after egg consumption were excluded.

The protocol for oral immunotherapy consisted of an initial-day dose escalation, a build-up phase, and a maintenance phase involving ingestion of up to 2 g of egg-white powder (equivalent of about one-third of an egg) daily.

Factors that were found to be associated with sustained unresponsiveness at 24 months were higher egg-specific IgG4 antibody levels at 10 months, smaller wheal diameter on skin-prick allergy testing at 22 months, and a decrease in wheal size from baseline to 22 months, the investigators noted.

Oral immunotherapy in this study was generally well tolerated, with adverse events occurring most frequently in association with oral-immunotherapy dosing. Most of the events were mild (grade 1), with only 1% being graded as moderate (grade 2). No severe adverse events occurred. Most events were oral or pharyngeal, and were associated with 25% of the 11,860 doses of oral immunotherapy, and with 3.9% of the 4,018 doses of placebo. The rate of symptoms decreased to 8.3% of 15,815 doses in the oral immunotherapy group after 10 months.

The findings could have important implications, given that the cumulative prevalence of egg allergy is approximately 2.6% by 2.5 years of age, and that egg avoidance (which is difficult and can adversely affect quality of life) is the only available treatment for egg allergy, investigators said.

However, for oral immunotherapy to be recommended as a standard of care, it is important to better define risks, compared with allergen avoidance; to determine the dosing regimens with the most favorable outcomes; to identify the patients most likely to benefit; and to develop postdesensitization strategies, the investigators concluded.

This study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health–National Center for Research Resources Clinical Translational Science Awards and Clinical Research Centers. Dr. A. Wesley Burks has been a consultant for companies including Dannon Co. Probiotic, McNeil Nutritionals, Merck, the Food Allergy & Anaphylaxis Network, and Novartis, and has grants or grants pending from the Food Allergy Initiative, the NIH, the National Peanut Board, and others. Some of his associates were consultants for companies including DBV Technologies, Allertein Therapeutics, and Sunovion, or received grants from various companies; other associates had no relevant financial disclosures.

CLARIFICATION 7/20/2012: The institutional affiliation of Dr. Burks has been updated to reflect his current position.

Oral immunotherapy using egg-white powder represents a highly promising therapeutic intervention for children with egg allergy, according to findings from a randomized, placebo-controlled trial reported online in the July 19 issue of the New England Journal of Medicine.

After 10 months of immunotherapy, none of the 15 children with egg allergy who received placebo as part of the double-blind study passed an oral food challenge of 5 g of egg-white powder, whereas 22 (55%) of 40 children who received oral immunotherapy passed the oral food challenge and were considered to be desensitized. At 22 months, 30 (75%) of the 40 children who received oral immunotherapy passed an oral food challenge with 10 g of egg-white powder, Dr. A. Wesley Burks, chair of the department of pediatrics at the University of North Carolina and chief physician of N.C. Children’s Hospital, his colleagues reported on behalf of the Consortium of Food Allergy Research.

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Of the 30 children who passed the oral food challenge at 22 months, 29 were rechallenged at 24 months with 10 g of egg-white powder, followed 1 hour later with one whole cooked egg (after having discontinued immunotherapy and egg consumption for 4-6 weeks); 11 (28%) passed the challenge and were considered to have "sustained unresponsiveness," the investigators reported (N. Engl. J. Med. 2012 July 19 [doi:10.1056/NEJMoa1200435]).

These 11 children then were instructed to add egg to their diet ad libitum. No adverse events were reported at the 30- and 36-month follow-ups.

Study participants were children aged 5-18 years (median, 7 years) with a convincing clinical history of egg allergy and a serum egg-specific IgE antibody level of more than 5 kU/L for those aged 6 years and older, and 12 kU/L or more for those aged 5 years. Those with a history of severe anaphylaxis after egg consumption were excluded.

The protocol for oral immunotherapy consisted of an initial-day dose escalation, a build-up phase, and a maintenance phase involving ingestion of up to 2 g of egg-white powder (equivalent of about one-third of an egg) daily.

Factors that were found to be associated with sustained unresponsiveness at 24 months were higher egg-specific IgG4 antibody levels at 10 months, smaller wheal diameter on skin-prick allergy testing at 22 months, and a decrease in wheal size from baseline to 22 months, the investigators noted.

Oral immunotherapy in this study was generally well tolerated, with adverse events occurring most frequently in association with oral-immunotherapy dosing. Most of the events were mild (grade 1), with only 1% being graded as moderate (grade 2). No severe adverse events occurred. Most events were oral or pharyngeal, and were associated with 25% of the 11,860 doses of oral immunotherapy, and with 3.9% of the 4,018 doses of placebo. The rate of symptoms decreased to 8.3% of 15,815 doses in the oral immunotherapy group after 10 months.

The findings could have important implications, given that the cumulative prevalence of egg allergy is approximately 2.6% by 2.5 years of age, and that egg avoidance (which is difficult and can adversely affect quality of life) is the only available treatment for egg allergy, investigators said.

However, for oral immunotherapy to be recommended as a standard of care, it is important to better define risks, compared with allergen avoidance; to determine the dosing regimens with the most favorable outcomes; to identify the patients most likely to benefit; and to develop postdesensitization strategies, the investigators concluded.

This study was supported by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health–National Center for Research Resources Clinical Translational Science Awards and Clinical Research Centers. Dr. A. Wesley Burks has been a consultant for companies including Dannon Co. Probiotic, McNeil Nutritionals, Merck, the Food Allergy & Anaphylaxis Network, and Novartis, and has grants or grants pending from the Food Allergy Initiative, the NIH, the National Peanut Board, and others. Some of his associates were consultants for companies including DBV Technologies, Allertein Therapeutics, and Sunovion, or received grants from various companies; other associates had no relevant financial disclosures.

CLARIFICATION 7/20/2012: The institutional affiliation of Dr. Burks has been updated to reflect his current position.