By Abby S. Van Voorhees, MD,
May 01, 2014
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Donald V. Belsito, MD, about his recent Journal of the American Academy of Dermatology article, “Cutaneous delayed-type hypersensitivity in patients with atopic dermatitis: reactivity to topical preservatives.”
Dr. Van Voorhees: Atopic dermatitis (AD) and contact dermatitis — didn’t we used to think that these two conditions rarely occurred in the same person? Do you feel that the dry skin seen in these patients is contributory in some way?
Dr. Belsito: That’s an interesting question because when the whole notion was that AD was a Th2-mediated disease and contact dermatitis was Th1, the presumption was that people with AD could not develop contact dermatitis because their whole immune system is skewed toward Th2. And then there was data in the literature showing that in individuals who were having acute atopic flares, their ability to be sensitized to allergens such as dinitrochlorobenzene was reduced. However, that data also showed that once their AD quieted down, they were able to be sensitized about the same as the normal population. Then in 2004 Donald Leung wrote an interesting article (J Clin Invest. 2004;113(5):651-657) where he showed that acute AD starts off as a Th2 disease, but as it moves on in chronicity it actually is a Th1 disease, probably because barrier disruption and scratching lead to a lot of pro-inflammatory cytokines. So what starts off as a Th2 process in the acute phase will switch to Th1 in the chronic phase, or at least that’s what he postulated.
Beyond that what you’re dealing with in atopics is barrier dysfunction and people putting a lot of things on their skin. So you have more frequent exposure in terms of the types of products being put on the skin and the greater ability for those products to penetrate through skin to the antigen-presenting cells and create allergy. In fact when we looked at our numbers, atopics were significantly more likely to have at least one positive patch test than non-atopic patients. This was just based on patch testing; we didn’t look at the relevance of the patch test reaction but just whether they could mount a delayed-type cellular-mediated hypersensitity reaction to allergens.
Dr. Van Voorhees: Were atopics at increased risk for all contactants in your study? Were there certain ones where reactions occurred with an increased frequency? Were any at a lower frequency? [pagebreak]
Dr. Belsito: There’s a power limitation to the study because of the number of patients that we had that met the Hanifin/Rajka criteria for AD, so we had some results that didn’t reach statistical significance. But as we published last year, the most striking thing among atopics was an incredibly high incidence of metal allergy, particularly for nickel, but also for cobalt and chrome (J Am Acad Dermatol. 2013 Aug;69(2):232-7). The next group of chemical allergens responsible for reactions was the preservatives, the subject of this paper. And then we have a paper that has been published online where we looked at surfactants, where we found that atopics are significantly more likely to react to a surfactant called cocamidopropyl betaine (doi: 10.1016/j.jaad.2013.12.009). Beyond that we’re seeing trends but because of our numbers we’re not reaching statistical significance with allergens other than the metals, preservatives, and surfactants.
Dr. Van Voorhees: Are you sure that this is a true contact dermatitis rather than just an irritant dermatitis to the formaldehyde?
Dr. Belsito: I think it’s definitely a true contact dermatitis. There was no significant difference between atopics and non-atopics in terms of their reactivity to formaldehyde in patch testing. But we saw significant differences in reactions to the formaldehyde releasers. This is not what you would expect if this were an irritant phenomenon. It’s a real phenomenon that came up for most of the formaldehyde releasers.
The sole exception was diazolidnyl urea where there was a trend for atopics to react but it wasn’t statistically significant. And again, that’s probably because we lost power due to our population size which is, by nature, limited. But I don’t think it was an irritant reaction — because if it was, we should have seen formaldehyde significantly more positive in the atopic population.
Dr. Van Voorhees: For those of us who could benefit from a refresher, what are some names of well-known formaldehyde releasers?
Dr. Belsito: Quaternium-15 is probably the major one that we see allergic reaction to. And then there’s imidazolidinyl urea, DMDM hydantoin, 2-bromo-2-nitropropane-1,3-diol, and diazolidnyl urea — those are the major formaldehyde releasers you see in personal care products. We saw increased reactions among atopics to quaternium-15, imidazolidinyl urea, DMDM hydantoin, and 2-bromo-2-nitropropane-1,3-diol. We did not see increased reactions among atopics to diazolidnyl urea or to formaldehyde itself. [pagebreak]
Dr. Van Voorhees: Do you have a theory as to why people are becoming allergic to these formaldehyde releasers but not to formaldehyde itself?
Dr. Belsito: It’s simply because formaldehyde is not used anymore as a preservative in a lot of personal care products. It’s pretty rare to see it in anything that an individual would be exposed to short of more commercial or industrial products like paints. So I think that it’s really an issue of exposure. They’re simply not being exposed to formaldehyde whereas they’re being exposed to a lot of topical products, including topical medicaments, that are preserved with formaldehyde releasers.
The surprising thing to me was that for parabens we didn’t see a difference between the atopic and non-atopic population, and we didn’t have a single atopic patient who reacted to paraben mix. This is surprising because Alex Fisher coined the term paraben paradox, based on the fact that in guinea pig maximization studies parabens were predicted to be very strong sensitizers. When that data came out in the 1970s companies pulled parabens out of their products, which led to them having other issues with other preservatives. Now they have gone back to parabens, which have become the most frequently used preservatives. Alex thought the paraben paradox came about because parabens don’t penetrate the stratum corneum very well. But we know that 50 percent of atopics have a filaggrin mutation and even those who don’t have the mutation have barrier disruption and enhanced transepidermal water loss. And yet we’re not seeing this issue with parabens in our patient population. So that led us to recommend, and that’s all it is, that when you’re dealing with atopics you preferentially use ointments without preservative systems or, if you are going to use something with a preservative system, it appears that a paraben-based preservative system is much better than any of the formaldehyde-releasing systems for atopic patients.
Dr. Van Voorhees: Is there a practical take away for our patients with atopic dermatitis?
Dr. Belsito: From this paper the important thing is that they try to avoid products containing formaldehyde releasers, preferentially use ointments, and if providers are going to use topical preparations that need to be preserved with a biocide, they should use paraben-preserved ones. From the preceding paper we published on the more significant increase in metal dermatitis, we also recommended that atopics consider not having body piercing or metallic-based tattoos.
Dr. Belsito is the Leonard C. Harber Professor of Dermatology at Columbia University College of Physicians and Surgeons. His article appeared in the January issue of the Journal of the American Academy of Dermatology; J Am Acad Dermatol. 2014 Jan;70(1):102-7. doi: 10.1016/j.jaad.2013.08.046. Epub 2013 Nov 9.