Immunotherapy: a history of histamines

"Winter" here in the San Francisco Bay Area may not be severe by anyone's standards, but there's a definite change in the air that has flipped some sort of switch for me and Voov. It's always been this way, mysterious: changing weather makes eczema worse. Toward winter, it's probably reduced humidity in the air; in spring, there's probably pollen. Can't do much about either! Slather on more moisturizer after November, maybe, but it's not a 100% remedy. And as far as antihistamines go for pollen: completely useless, in my experience.

So here we are, skin suddenly tighter and drier, the red excoriations on our hands and wrists. But neither of us is going through an extreme flare.

I ran out of Eucerin on the weekend, and picked up a jar of generic moisturizer at CVS. You know the kind. It's the store brand stuff stacked next to the Eucerin, and the price tags read "Eucerin: $15.99" "CVS Moisturizing Creme: $9.99." You get what you pay for. The problem is, the cheap stuff may LOOK the same as Eucerin, but it sucks. It's thinner and slippery and wears off fast. I have to relearn this the hard way every six months or so.

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I want to share this review with you. It covers the history of our understanding of how immunotherapy works. The senior author is Mitchell Grayson, the scientist from the Medical College of Wisconsin who gave a presentation on eosinophils at the recent annual meeting of the American College of Allergy, Asthma, and Immunology.

The review is only eight pages including two of references, but it's encyclopedic. It follows immunotherapy all the way from its inception in 1911 (Leonard Noon's paper in the Lancet on injecting hay fever patients with grass pollen extract) to the current day. The authors explain how the therapy has remained essentially the same, but our understanding of how it works has evolved to become ever more complex as scientists have laid bare the secrets of the immune system.

In short: in the 1930s, scientists realized that patients given immunotherapy develop "blocking antibodies" that hinder the overeager allergic response. In the late 1960s, they learned that immunotherapy stabilizes mast cells and basophils and reduces the quantity of histamine released when patients encounter allergenic triggers. In the 1990s, after the discovery that there are at least two subtypes of helper T cells, scientists realized that immunotherapy partially shifts the T cell population in allergic patients from the allergy-related type 2 to the infection-related type 1. And in the mid-2000s, regulatory T cells were discovered; immunotherapy apparently increases the number of regulatory T cells that inhibit type 2 helper T cells.

Over time,  immunotherapy has been refined. With greater understanding of how the mucosal membranes process allergens, scientists developed sublingual immunotherapy, in which the allergens are placed under the tongue and absorbed into the tissue, where they are taken up by dendritic cells. (Straight-up oral immunotherapy, where the patient swallows the substances, is a bust.)

And, for asthma patients at risk of severe allergic reactions, doctors now administer immunotherapy along with the monoclonal anti-IgE antibody "omalizumab." Which is produced by Genentech, naturally, and costs $10,000 to $30,000 a year. I wonder, within the US, which insurance plans cover this, and whether the product is available outside the US. It's relevant to eczema because it appears to be quite effective-- it might become cheaper over time (e.g. after the patent expires) or other companies might develop alternatives to take excess IgE out of our systems.

Badge of honor

At the bottom of the right-hand column you'll notice a snazzy new badge. End Eczema has been recognized! By that fine institution, www.medicalassistantdegree.com. If you click on it, as I did, you'll end up on a page listing nineteen blogs. "Score!" I thought to myself. "A whole host of eczema blogs-- the vibrant blogger community I always knew was out there!"

Unfortunately, on closer inspection, all of the other blogs, if not dead, either have been quiet for months or clearly have no scientific merit. Or any kind of merit. Sigh. Eczema Mom and Cindy: L'eczema blogging community, c'est nous.

But I'll wear the badge with pride, at least until a better one shows up. It's like having a degree in blogging from the University of Phoenix.

Speaking of academic institutions, today I found a syndicated newspaper column in the LA Times online, written by Henry Bernstein, senior lecturer in pediatrics at Harvard Medical School. A reader asks him "what can I put on my 3-year-old grandson to treat his eczema?" According to Bernstein, those of us with eczema can expect to have

• Dry, scaly skin
• Plugged hair follicles that make bumps (usually on the face, upper arm and thighs)
• Swelling around the lips
• Darkening of the skin around the eye

Dry, scaly skin: check. Plugged hair follicles? Swollen lips? Dark circles around the eyes? Is this how they teach dermatologists at Harvard to diagnose eczema? I'd rather my dermatologist had a diploma from the University of Phoenix. Oh yes, Bernstein does get around to answering the question in the end: you should be putting moisturizer on your grandson. Duh!

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As you can see, I have been inspired by the holiday spirit.

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I learned that the company 23andMe in Mountain View, CA has a special deal out on personal genetic sequencing. For $99 you can send in your spit and find out your risk of developing 175 different conditions. Atopic dermatitis is one of them. If you're reading this, I suspect you already know what your risk is-- but FYI, they appear to be testing whether you possess one of the two common mutations of the filaggrin gene.

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In my last post, I mentioned that another Bay Area company, Anacor, has an interesting anti-inflammatory drug in the pipeline, a boron-based compound. I should have mentioned that I find it interesting because it is most likely not a steroid, and won't have the side effects of steroids-- though it will inevitably have other side effects. I'd like to know how it works and what strength it might be (compared to the US steroid scale).

And something else I'd like to know: is anyone making an anti-ITCH cream instead of an anti-inflammatory? Is anyone addressing itch neural fibers rather than just reducing the blood flow to the skin?

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Here's a story about another experimental drug: this lady, in England, suffered from hand eczema that became debilitating-- affected her right hand so that she could hardly use it for anything, and looked so nasty she had to wear a Michael Jackson-style single black glove. She was put on steroids, of course, and given UV treatment, which did nothing. What appears to have put her eczema in remission is a drug called alitretinoin, which is sometimes prescribed for Kaposi's sarcoma.

What is alitretinoin doing to relieve eczema? I'm not sure. At least it's not a complete shot in the dark for a dermatologist to prescribe: here's a story describing how a clinical trial of alitretinoin in Europe and North America cleared up hand eczema in ~50% of treated patients. I believe hand eczema (on the palms, not the backs) can often be triggered by rubber gloves or exposure to certain metals. A few years ago, I had eczema on the soles of my feet-- I think it was the hot, humid climate of Washington, DC, that was to blame-- and it was intolerably itchy. Denise Hyland has my full sympathy.

The holiday challenge begins

Tomorrow in America, the first wave of the great tide of holiday craziness will wash over us-- beginning with the inevitable turkey dinner. I'm not a native-born American, so although I have come to love Thanksgiving, I'm still not used to the idea of the entire month of December being given over to overeating and indulgence. At work, the holiday parties start the Monday after next. It's almost impossible to avoid eating or drinking all kinds of things that trigger eczema: chocolates, booze, spices. More booze. And eggnog. I used to like eggnog--in fact, I still do--but a few years ago, after having had a skin prick test that showed I reacted to raw egg white, I suddenly realized that eggnog has RAW EGGS in it, and that's why I was always scratching like a monkey after a glass or three. (Sometimes the eggnog has booze in it, too.)

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I'm always interested when there's a story in the news about someone with eczema. Here's a recent one from Scotland, about a five-year-old girl in Linlithgow (outside Edinburgh).

Despite being so young, Gaelle, a primary one pupil, has used her experiences of atopic dermatitis to educate her classmates and teachers, who have to help her apply her skin cream and bandages every day at school.

She even used her birthday party to fundraise for the cause.

At five years old, she can't have come up with these ideas on her own. She's got some parents who are taking the offensive. It's a good idea. When the kids in Gaelle's class are older and start to cast about for others to tease, they'll at least have had some hands-on experience with eczema and some understanding of what it means to someone who lives with it, and they may not be so quick to treat her as an alien.

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Another news item: UAS Labs, a probiotics company in Minnesota has won an award for "Probiotic Customer Value Enhancement." Thrilling stuff, you will agree. What caught my attention was that UAS makes five "formulations" of live bacteria for specific conditions, and one of them is atopic dermatitis. What's in the AD formulation? A mix of Lactobacillus acidophilus (the yogurt bacterium) and Bifidobacterium lactis. Both are common gut bacteria, but also common probiotics. UAS worked with a scientist in Ukraine on a study to explore how their formulation might improve AD in kids aged one to three. It's not clear whether UAS funded the study; I expect they did, because otherwise there'd be no need for someone in Ukraine to obtain UAS's formulation. Still, the results of the study--presented at a symposium, not published in a journal--showed that eczema symptoms were reduced by 34% on a standard scale for kids taking the probiotics, versus being reduced 19% for kids taking placebo.

If these results are real, which is not at all certain, then it's interesting to think how intestinal bacteria could help reduce eczema. Are they helping the body digest milk proteins or sugars that would otherwise cause an inflammatory response that, in susceptible people, manifests in the skin? Lactose intolerance is widespread. Perhaps it's linked to milk reactions in eczema. I don't know at this point.

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And a novel topical anti-inflammatory cream/ointment is entering phase 2 trials in eczema patients. Anacor is a San Francisco Bay Area company that makes drugs based on its trade secret, a "boron chemistry" platform. Phase 2 is VERY early in drug discovery, but it's interesting to watch this sort of thing emerge. They seem to have a good idea of what their drug is doing to reduce inflammation.

I'll be off tomorrow. We may be lucky and hear from Dr. Sib. She's Canadian and had her Thanksgiving about a month and a half ago. Unless she's working the midnight-to-8 am ER shift, what possible excuse could she have for not writing?

Sunflower seeds and coconuts-- good for more than eating?

In the email Peter Lio sent me the other day, he mentioned that he is getting excited about the potential of two natural products: sunflower oil and coconut oil. He sent me references to two research papers on the topics.

Since sunflower and coconut oils are both edible, I imagine the risk of adverse effects (unless you're allergic to them) is pretty small. And they're oils, so that means they can work as emollients, and soften the skin and reduce transepidermal water loss. I'd like to know how they work in this dimension compared to commercial moisturizers-- does a lot rub off? (I have a problem with my clothes getting greasy) and how often do you have to apply them?

The most interesting thing is that these oils may have special properties; apparently coconut oil contains a fraction with antimicrobial activity, and in one study with a small number of patients, was shown to reduce Staph. aureus colonization.

Sunflower seed oil may be slightly more complex; or perhaps it's just that in the review paper I read, the authors covered a lot of research considering different aspects of sunflower seed oil. Let's call it SSO for short. The point of review's authors is that SSO is actually good for eczema treatment, but allow me to digress for a paragraph.

/Start digression The main component of SSO is the "essential" fatty acid linoleic acid. The authors point out that linoleic acid can be converted to arachidonic acid, a precursor of prostaglandin E2, which they say is a "known modulator of cutaneous inflammation." Indeed it IS a modulator-- PGE2 is a vasodilator and used clinically to induce erections and hasten birth. The review paper considers pediatric use, though, so let's assume those aren't going to be issues. (I'm just pointing out that you can't vaguely say "oh, this lipid turns into something that is INVOLVED in modulating inflammation," and expect me to rub it all over my skin when the compound concerned CAUSES inflammation.) /End digression

The lead author of the study works at Rady Children's Hospital at UCSD, home to a famous pediatric eczema center, so he's probably not a kook. Let's look at some positive aspects of SSO the authors highlight: a number of studies show that in a 2% formulation, SSO has anti-inflammatory properties equivalent to a "mid-potency topical steroid" and, when used in tandem with an actual steroid, can enable the same effective strength for 25% of the original steroid dosage.

This former grad student has some questions for the speaker.

• Steroids are related to cholesterol-- is anyone sure that SSO doesn't contain a certain percentage of "natural" steroid that is causing these effects? (And could have the same side effects as an "artificial" steroid?)
• Is there more than one active component? One or more of the major lipids, or some drug-like compound present at a small percentage?
• I'd like to see a breakdown of what's in that "2% sunflower oil distillate." The scientists seem to be mixing SSO with a bunch of lipids that are essentially the same thing as SSO, but also adding some nameless "phytosterols" and vitamin E.
• Who decided that 2% formulation was the ideal composition? And, most importantly, where's the dose dependence data? In drug trials, it's key to show that the magnitude of therapeutic effect increases as you increase the dosage of drug-- that indicates that it's the drug that's making it happen, and not something else you hadn't considered. I don't see any mention of dose dependence in this review.

OK, I've evidently developed a skeptical reaction, which I honestly didn't have to begin with. Sunflower seed oil-- I'm going to need some more evidence that there's anything behind the claims. It's not going to be anyone's miracle cure, but there's always the possibility that a natural product is hiding some magical ingredient.

Aveeno stonewalls; and introducing eosinophils, the "riflemen" in your skin

So I wrote to Aveeno the other day, asking them two very simple questions:

1. What makes the Eczema Therapy line different from any of their umpteen other moisturizers?
2. What data can they show to prove that it works?

I found out that Aveeno is owned by Johnson and Johnson, and that, despite Aveeno's friendly Facebook video, J&J is as terrible at customer relations as any giant corporation.
Answer #1:

...the Aveeno® Advanced Care™ Moisturizing  Cream is different in these ways:

Essential ACTIVE NATURALS®:
-Pure oat essence and natural colloidal oatmeal to soothe skin
-Ceramides to help enhance skin's ability to retain moisture
-Plus moisture-rich oat oil

However,  this product has since been discontinued.

Not particularly helpful, since that wasn't the product I asked about. I wrote them again, repeating my original question. We'll see what they say. The active ingredient in the Eczema Therapy lotion is 1% colloidal oatmeal. Hardly revolutionary. Is it any different from anything else Aveeno puts out? Probably not.

Answer #2:

We are very sorry, but our company policy prohibits disclosing this type of information. Most of our research, marketing and sales information is proprietary, as is information regarding our ingredient percentages and formulations of individual products.

So: none of your business.

I did call the FDA to see if there were any instances on record of an official FDA warning letter being sent to Aveeno (recall, Peter Lio told me Aveeno had come out with this line a few years ago, and got their hand slapped because they were making an unsubstantiated therapeutic claim).  I was shuttled from the cosmetics division to the drug division-- colloidal oatmeal is classed as a drug, I found out, with the magical property of "skin protectant." There are no warning letters on record. I'm guessing that perhaps there was some low-level communication from the FDA to Aveeno that resulted in them listing colloidal oatmeal as the active ingredient.

The ridiculous thing is that someone at some point had to register oatmeal as a drug, which must have involved all kinds of safety trials.

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Last week, you may recall, saw the end of the annual conference of the American College of Allergy, Asthma, and Immunology. On the Saturday before last, there was this session in the afternoon called the "Great Atopic Dermatitis Raft Debate." I have now found out what this was about, or more specifically, what "raft" is doing in the title. From the conference brochure:

Premise: Experts involved in atopic dermatitis management are adrift in a life raft. There's enough food and water in the raft for only one to survive, and the surrounding waters are teeming with sharks. Each expert has exactly 15 minutes to make his case. Come and see who gets tossed to the sharks!

This explains why sharks feature so prominently in the Powerpoint of Mitchell Grayson, MD, one of the presenters. I wrote to all four professors in the debate, asking if they could send me their presentations and save me paying $350 to the ACAAI (now there's a posse of sharks) for the conference DVD. Only Grayson obliged. So I declare him, by default, the winner-- we toss Mark Boguniewicz, Donald Leung, and Lawrence Schwartz off the raft.

Grayson represented "eosinophils" in this epic tussle. Eosinophils are a type of white blood cell. My PhD topic had an immunological focus (helper T cells) but I really never heard diddly about eosinophils, so I was excited to go through his presentation. Let me share the gist:

On the battleground of eczema, eosinophils are the "riflemen," according to Grayson.

Eosinophils are, he argues, the cells most responsible for eczema. (Keep in mind that he was trying to win a 15-minute debate.)

Eosinophils, triggered through a signaling chain that begins with mast cells and goes through T cells, are the ones who "shoot" pathogens, destroying them with reactive oxygen species (e.g. peroxides) and "cytotoxic granules," aka poison. We'll ignore the fact that history usually holds the generals responsible for what the army does in war, although recent events at Gitmo show that we may not have enough perspective on that conflict yet.

Activated eosinophils are found in the middle layer of skin in patients with eczema. In normal skin, eosinophils have no business being there. Some scientists think that eosinophils contribute to skin irritation by releasing their toxic payloads. Here's a microscopic view of an eosinophil, from Grayson's Powerpoint:

You can see a cytotoxic granule highlighted. Some evidence that skin eosinophils may play an important role in eczema: urinary levels of eosinophil products are proportional to the severity of eczema; treatment of eczema with tacrolimus and pimecrolimus reduces the number of skin (but not blood) eosinophils; reduction of blood eosinophils has no effect on eczema. One experimental mouse model develops eczema only if eosinophils are present.

So there's a lot of circumstantial evidence against eosinophils. Our real question: OK, say you prove eosinophils are the key-- how can we target them to prevent eczema?

On that, Grayson has no answer. We can forgive him, though. It seems that dendritic cells and adhesion molecules are really what he specializes in.