Jon Hanifin: Barrier defects come first in eczema; allergies follow

Atopic dermatitis is a disease that arises primarily because of a breakdown in the barrier properties of the skin, and allergic reactions typical of AD are a consequence of this breakdown, Jon Hanifin told an audience last week at the annual meeting of the American Academy of Dermatology, held in San Diego.

Hanifin is one of the US's leading dermatologists, and practices at Oregon Health and Science University in Portland. He was kind enough to send me the Powerpoint of his talk, which I wanted to read because I figured from its title ("AD Pathogenesis: What's New") that it would give me a good picture of the field.

His talk was encyclopedic and technical and I'm not going to attempt to cover the whole thing. But it did make clear to me that the standard model for how eczema arises and develops is in a state of flux.

For a long time, it was thought that allergy was the dominant factor in eczema. But a key paper in 2006 linked higher risk of developing eczema and asthma to mutations in the gene coding for the protein filaggrin. Filaggrin is a long protein, consisting of a string of subunits, that has an important structural role in skin cells, especially in the uppermost layer (the stratum corneum), and also gets broken down at the surface into something called "natural moisturizing factor." From that first paper came a flood of research into filaggrin, which has helped paint a fuller picture.

One thing that jumped out at me from Hanifin's talk was that the relationship between filaggrin mutation and eczema is not simple. The severity of eczema depends on where mutations are within the protein; it's possible to have more than one mutation, which greatly increases the likelihood that you'll get eczema.

Hanifin cautions that filaggrin is not the only genetic culprit in the origins of eczema. Mutations in certain other proteins can compromise the skin barrier.

If filaggrin is messed up, your skin barrier will be too--it'll be leaky--and this means that your body gets exposed early on to a wide variety of antigens that it otherwise wouldn't be. Recently I wrote about the "hygiene hypothesis," which posits that it's good for kids to get exposed to germs because that helps prevent allergies later on, but it seems that it's not good to get exposed to too many germs, because that leads to allergies later on. There's a Goldilocks-just-right amount of germs that your immune system needs to encounter to develop properly. Hanifin laid out the current thinking, which goes as follows:

• Defects in skin cell proteins let in irritants, microbes, allergens
• This causes skin cells to release a signaling molecule called "TSLP"
• TSLP stimulates white blood cells to develop an immune system dominated by type 2 helper T cells (which act via antibodies and inflammation, rather than by macrophages that eat pathogens)
• Th2 cells induce production of IgE antibodies, and then you have classic allergies linked to eczema.

It's just a logical progression. Allergy caused by skin defects seems generally to make more sense to clinicians and researchers these days than skin defects caused by allergy.

Now, is it possible to have atopic dermatitis without abnormal IgE/Th2? Hanifin replied by email:

Yes, roughly 20% of AD patients have typical eczema without any Th2/IgE abnormalities or asthma, etc. ( I call that "pure AD" but allergists tend to call it "intrinsic.") It's been known for years and is the reason we've always doubted that allergy was causative for the skin disease--IgE is clearly involved with hay fever, food allergy and some cases of asthma that usually accompany AD.

Hanifin lays a lot of stress on the precise definition of food allergy, which is specifically defined as an adverse health effect, rather than an adverse immune response. (He refers you, and me, to the NIAID Food Allergy Guidelines.) A positive IgE test for a food doesn't necessarily mean you're allergic. You have to get ill after eating something to be truly allergic to it. Hanifin clarifies:

Not necessarily ill, but usually rapid onset of hives, maybe nausea, cough--sometimes anaphylaxis...The tests are often imprecise and not everyone with high specific IgE levels reacts to that food. Whether they have become tolerant or never were allergic can only be speculated.

My guess is that Hanifin and other dermatologists are increasingly under siege from overinformed patients such as myself who have garnered information from the internet and are now demanding that their doctors conduct allergy tests to nail down the one or two things they're convinced must be causing their eczema. In his email, he comments that there are currently "enormous financial incentives associated with the belief of allergy causation of AD." Patients, and the insurance system, are paying a lot of money for test results that aren't useful.

What I'd like to see an explanation of is why most children grow out of eczema. What is it that's happening to their skin barrier and immune systems as they mature over the ages of 3-8 or so that is freeing them from the disease? Maybe, if we knew, we could capture and intensify that process and apply it to at-risk children and adults who have remained affected.

Does getting dirty make a kid healthier? Yes, if he or she is a laboratory mouse

If you're like me, you think that it's healthy for kids to play in the dirt and wrestle with dogs and suffer through a cold now and then. I think of it as giving your immune system a workout. That way, when it runs into something like the H1N1 flu virus, it's got some muscles built up--in the form of lots of B and T cells and antibodies. That's the hope.

The immune system's more complicated than that, but the basic theory that it's good for kids to eat dirt is known as the "hygiene hypothesis." The subtlety, according to the theory,  is that a lack of exposure to microbes prevents the immune system from developing a tolerance for certain antigens, and leaves the body more likely to develop auto-immune diseases. Last week the hygiene hypothesis got some support in the form of laboratory experiments conducted on mice by a team of researchers in Boston and Kiel, Germany.

In their paper, published in Science [nice news story in Nature too], the scientists explain how they worked with two types of mice--one, "germ-free," devoid of any bacteria or protozoa or viruses (except viruses already integrated into their DNA), and the other, "specific-pathogen-free," which they don't describe very well but which you assume have well-established symbiotic gut microbes but aren't infected with any diseases. The germ-free mice, the authors find, have increased numbers (compared to the SPF mice) of white blood cells called "invariant natural killer T cells," which can detect certain kinds of molecules associated with infection; cause inflammation when they're activated; and have been linked to both inflammatory bowel disease (IBD) and asthma.

The germ-free mice had increased numbers of NKT cells in just their colons and lungs, and were far more susceptible than the SPF mice to laboratory models of asthma and IBD.

But when the scientists exposed pregnant germ-free mother mice to the same living conditions as the SPF mice, so that they and their newborns could acquire a population of gut microbes, the thus-exposed "germ-free" baby mice went on to develop relatively normal populations of NKT cells, and were protected from getting asthma and IBD.

However, allowing adult germ-free mice to build their own gut flora did not protect those mice from asthma and IBD. So it seems there's a window in which young mice must be exposed to microbes--to play in the dirt, as it were--if they are to get any benefit.

Because this paper was published in Science--about as high-profile as it gets--I'm guessing that clear evidence supporting the hygiene hypothesis is sparse. What conclusion could you draw from this research?

No human child, excepting the Bubble Boy, is brought up in an environment remotely resembling that in which germ-free mice are maintained. We're all crawling with bugs inside and out; dirty whether we like it or not. But Western society is quite keen on taking antibiotics to treat bacterial infection. And most antibiotics are pretty indiscriminate in what they kill. That's why the pharmacist warns you that your digestion may be upset while you pop Amoxicillin. It clears out your intestines.

So giving very young children oral antibiotics unnecessarily could be doing them harm in the long run by depriving them of gut microbes during a critical window--and those kids could grow up more likely to develop asthma and IBD.

Does the hygiene hypothesis, and this research in particular, apply to eczema? I put this question to Jon Hanifin, MD, a dermatologist at Oregon Health Sciences University, and am hoping to hear back from him.

[Monday, March 26] And here are his replies:

Question 1 : is this research relevant to atopic dermatitis? (are natural killer cells involved in AD?)

JH: It would be pretty speculative to claim relevance to AD but the "hygiene hypothesis" has been suggested for all the atopic conditions for many years and maybe this model will provide some some basis for testing the hypothesis. NK cells have probably been studied in AD just like all the others but much of the work with any of the T cells can be misleading so it is best to step back and look at the larger picture.

Question 2: if so, is there anything usable for patients, extrapolating from the results; could it possibly be that infants in modern society/urban centers aren't being exposed early on to the "right" mix of/number of nonpathogenic microbes?

JH: Not much at this point--presumably infants get exposed to all the microbes parents carry.  The idea that farm kids get a broader palette seemed to have some validity for respiratory allergies but not much for AD. The greater AD incidence in urban kids might reflect more barrier damage from use of irritating/drying skin care products.

Blood tests for food allergies/sensitivities that may cause eczema

Just out in the Canadian Medical Association Journal: a primer, presumably for doctors [media summary] on how to handle patients who arrive in the doctor's office clutching printouts of blood tests taken to find what foods might be causing trouble for them.

I'd imagine this happens all the time. I don't blame patients at all. Who cares most about your health? You do. Do you think your medical providers, whatever system you use, are doing as well as they could for you? Probably not. So if you've got a chronic condition that seems to be related to what food you eat, you get a blood test done to try to find the culprit(s).

There's more than one problem with this, however. Most patients don't understand the difference between food allergy, reaction, and sensitivity. The primer's author, Elana Lavine, briefly explains:

Food allergy is an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. Nonimmunologic adverse reactions to food are termed food intolerance and include conditions such as lactase deficiency, dietary protein–induced enterocolitis syndromes and eosinophilic gastrointestinal disease. Food sensitivity is a nonspecific term that can include any symptom perceived to be related to food and thus may be subject to a wide range of usage and interpretation.

Eczema patients (in my understanding), are usually subject to the first and third categories. We probably have IgE antibody-based allergies to one or more foods (in addition to pollen and pet dander). And our skin inflammation is exacerbated by anything that causes increased blood flow at the surface, such as spices, alcohol, and histamines from fermented or aged foods such as Parmesan.

Lavine says that many patients get blood tests based on measuring levels of IgG --a separate class of antibodies from IgE. But, she says,

neither total IgG nor IgG4 [a subclass] levels correlate with food allergy as shown on double-blind placebo controlled food challenges.

IgG4 floating around in our systems may just mean that we have been exposed to a food and become able to tolerate it.

I did a quick web search and found a company called ALCAT that claims to test for food sensitivity using their proprietary technology, which measures how white blood cells change size when exposed to antigen. I'd have to consult an expert but I have trouble believing that results from such a test would truly reflect how your body is reacting--or not--to foods.

So what can you do to determine whether food is causing your eczema to flare up? Lavine says

Making the diagnosis of a specific food allergy may include the following: a full medical history, physical examination, skin prick testing, carefully selected food-specific IgE levels and oral food challenges to suspected food allergens in some instances.

There's no easy answer. To nail an allergy, you need the whole shebang. Avoiding a food entirely and seeing whether your eczema improves is a good start. The trick is, in my experience, to eat as few processed foods as possible so you can get control of the ingredients. Beware: even something as simple as soy sauce may contain wheat, for example.

[added later] I realized that I didn't address the topic of IgE tests. I don't think that a consumer (in the US) can get this test done without a referral from a doctor. The last time I asked an allergist about getting tested for IgE (the technology available at the time was RAST), he told me that "they" didn't do RAST on atopic patients because the circulating level of IgE was so high that it inevitably saturated the measurement no matter what they tested for. However, a quick Google search reveals that Quest Diagnostics now touts the ImmunoCAP blood test as a way to determine IgE allergy. Has anyone tried ImmunoCAP?

First global eczema Twitterparty a success

Yesterday I took part in what must have been the first-ever "Twitterparty" for eczema, initiated by Jennifer at Itchy Little World (on Twitter as @EczemaCompany) and moderated by Mei at Eczema Blues (on Twitter as @MarcieMom). It was a genuine pleasure to interact with so many concerned and involved people, even more so as this was a truly global event--Mei's in Singapore, where it must have been early morning, and Jennifer's in the UK, where it was 2 am. Here in California it was 6 pm. Pretty sweet for me, hey?

The hashtag was #4eczema. Mei's posted an extract of the proceedings on her blog. I was slightly delayed in joining because of my commute so you will see me joining halfway through (I'm @endeczema).

In short, it was what you'd expect from a hundred or so people dancing around a complex topic on Twitter. Everyone's got their own agenda (seemed like the majority of tweeps were parents dealing with their children's eczema) and, since eczema is such a complex disease and has so many manifestations and triggers, and everyone's experience is unique, you see a cornucopia of problems and partial solutions. Fortunately Mei did the best she could as a moderator--the session was organized, if you can say that, around a series of eight or so questions that she posed to the crowd. The tweets were loosely correlated with the questions.

Also Mei had arranged for four "experts"--who I take to be practicing dermatologists, since I haven't checked them out--to anchor the session and, presumably, keep discussion connected to reality. This definitely added some credibility. I imagine if there were no experts participating, the discussion might have gotten hijacked by alternative therapies.

The thing is, there were so many solutions that people suggested, that just from looking at the transcript you can see that eczema is an unsolved problem. (Or bag of unsolved problems.) It's clear that the best you can do is find out what your or your kid's triggers are, bathe and moisturize properly, and use pharmaceuticals to keep the flares down. Personally, I was interested to learn that Zyrtec might work against pollen allergies. I haven't tried it yet. It's an antihistamine, and I have found the antihistamines Claritin and Allegra do nothing for me, so I don't hold out hope--but I'm willing to try it the next time I have a flareup.

All in all it was definitely a success. (I liked the prize giveaways too--even if I'm not going to win anything, or don't necessarily want to, it makes me feel competitive and heightens my attention.) My impression is that there will be another Twitterparty in the future, perhaps arranged for a time more convenient for Europe or Asia. I look forward to it. This was a great opportunity to connect with concerned patients, parents, and doctors around the globe.

Quit it with the puns in media stories about eczema

Have you noticed that newspaper editors tend to choose what they think are funny titles for stories about eczema?

The latest that I've seen: "The itchy and scratchy show," courtesy of the Ottawa Citizen.

This annoys me.

Why? Because eczema is no joke to me.

Writers almost always use humor to show disrespect. That's why humor is the weapon of rebels in repressive regimes like the USSR & why those regimes ban books like "The Master and Margarita." But when you're not a rebel, you're a bully. And the victim of the humor has the right to decide the difference.

So some editor at the Ottawa Citizen is dissing me. Us. Is this deliberate?

Nah, he or she is just lazy. The story that follows the title, after all, is serious. But editors need to choose titles that are short, relevant, and grab the attention. That's why they resort to cliches. Lord knows, in my writing and editing career, I have been guilty of doing the same thing.

Cliches call up a whole host of tired, familiar associations, George Orwell said, "like cavalry horses answering the bugle." The itchy and scratchy show. The Simpsons. People with eczema are always scratching! Isn't it funny. Well, not really, but from the editor's perspective, their job is done.

Disrespect, though, means people less likely to take eczema seriously as a medical condition. It's been shown to reduce quality of life as much as diabetes. Would you laugh at someone with diabetes? Would you write "Victory in the bag for colostomy patients"? "Amputees stumped by latest setback"? Maybe, if you work for a British tabloid, but we know how much integrity those people have.

I've decided this is an us-and-them issue. Where is it OK to joke about eczema? Within the patient community, where we have to live with the condition. The National Eczema Association uses a bunch of cringe-worthy puns as titles for their stories and features. And thanks to the Citizen, I myself was inspired to use "the itchy and scratchy show" as an idea for a kid's onesie in a contest Jennifer is having on her blog It's an Itchy Little World. We own eczema, so we've earned the right to choose how we talk about it.

But the media? Odds are, you don't know what it's like to live with eczema. So write serious titles. It works for the New York Times.