Thursday, June 27, 2013

Surprise: Th2 cells, inflammation high in both allergic, non-allergic eczema

When I talked to Jon Hanifin last year he mentioned an intriguing fact: eczema comes in two general types. About 80% of atopic eczema patients have allergies and high levels of IgE antibodies. But twenty per cent of patients have eczema without allergies.

The technical term for allergic eczema is “extrinsic” atopic dermatitis; the non-allergic kind is “intrinsic” AD.

Production of IgE—and most antibodies—is activated by type 2 helper T cells. So scientists have generally assumed that extrinsic AD patients had overactive type 2 helper T cells. But new research shows that type 2 helper T cells are overactive in both intrinsic and extrinsic AD patients.

The scientists, led by Emma Guttman-Yassky at Rockefeller University in New York City, analyzed skin and blood samples from 42 extrinsic and 9 intrinsic AD patients, looking at molecular and cellular differences in the immune system and the skin.

They found that type 2 helper T cell activation is actually higher in intrinsic AD patients than extrinsic AD patients. In fact, markers of inflammation in general are higher in intrinsic AD.

Figure 6 from the paper. Scientists now resort to "word clouds" to convey the complexity of molecular biology!
The results are surprising. Patients with intrinsic AD generally do not go on to develop asthma or allergic rhinitis; yet if you just looked at their helper T cells you’d think they were guaranteed to experience even more severe allergies than those suffered by extrinsic AD patients.

So what's keeping down the IgE levels in intrinsic AD? In the paper, the authors speculate freely, but so far there is no answer.

It also appears that a special class of helper T cells known as type 17 (so-called because they produce the signaling molecule IL-17A) are also more active in intrinsic than extrinsic AD. It’s not clear yet how scientists might  use this knowledge to design therapies more specific than current T cell-suppressing options such as ciclosporin, which can have severe side effects.

The research suggests that future T-cell related therapies will likely be similar for intrinsic and extrinsic AD, despite the different nature of the disease in the two patient groups.

Hat tip to KMO.

Tuesday, June 25, 2013

Not a fan of eczema meta-studies, especially that antibiotics one

You don’t have to look far for an example of how the media can inflate a trivial scientific result into something that looks like important news.

Take last week’s report in the British Journal of Dermatology that exposure of newborns or infants to antibiotics increases the risk of them developing eczema. It was all over the mainstream media, with headlines such as “Report claims antibiotics cause eczema” and “Could Using Antibiotics As A Child Make You Develop Eczema?” I’m still seeing it on Twitter.

I think it’s almost criminally irresponsible to publish news like this when you just know thousands of parents will now hesitate to give their kids antibiotics. The kids will be the ones who suffer needlessly, when they must endure potentially life-threatening infections without treatment.

If giving a child antibiotics substantially increased the risk of developing severe eczema, then that news would be worth paying attention to. But that is not what the BJD paper concludes.

For a start, the paper is a meta-study: a review and summary of a large number of original population studies that other scientists already carried out.

Meta-studies are a great way for scientists to pad their publication records without getting their hands dirty with real research.

In my experience, a meta-study is suspect just because it exists. I don’t see meta-studies coming out in areas in which the science is indisputable (e.g., that UV from the sun causes skin cancer). I see them in areas in which there’s no scientific consensus and most likely the phenomenon under study has a very small real effect. In the field of eczema research, I see meta-studies published about vitamin D, probiotics, traditional Chinese herbal medicine, and so on.

The reason you see meta-studies in these areas is because the trials are all finding different results and someone wants to obtain a big picture of what is going on. Lots of noise and a small signal. If it was obvious what was going on, there’d be no point in a meta-study.

But one major question is how do you compare studies that are done with different aims and measures? This question is especially relevant for the field of eczema research, where there isn’t even a consensus about how to diagnose or measure atopic dermatitis. Not that long ago I went to San Diego as a patient representative to the HOME meeting (the third such get-together), at which researchers were trying to settle on a single standard survey form for measuring how bad a patient’s eczema is. In several meta-studies I have seen the authors mention (i.e. complain) about how difficult it is to draw conclusions from multiple eczema population studies.

Then, the conclusions of the meta-studies are usually weak. The results are almost always presented as “odds ratios,” which to me seem like mathematical sleight-of-hand to inflate very small results. In the antibiotics-early life meta-study, the researchers reported an odds ratio of about 1.4. What this means is you get the number 1.4 when you divide one number, the odds that a child will develop eczema if they get antibiotics, by another number, the odds the child will develop eczema if they are not given antibiotics. If you assume that the second number is about 2:8, or 20% (given that there’s a 20% chance a kid in general will get some kind of eczema) that means, for an odds ratio of 1.4, that there’s a 26% chance a kid given antibiotics will develop eczema.

Big deal, a 6% increase in risk—if you believe the meta-study, which is comparing 20 other studies that all used different methods and measures.

Is that worth risking your child’s life for?

Thursday, June 20, 2013

Three years in: what has the $42M Atopic Dermatitis Research Network produced?

In July it will be three years since the NIH awarded National Jewish Health in Denver, CO $31 million to create and administer the Atopic Dermatitis Research Network, a consortium of five academic sites across the US. A contractor, Rho Federal Systems of Chapel Hill, NC, won an $11 million contract to operate a center to coordinate statistics and clinical trials for the project.

That makes $42 million—spread over five years—which puts the project on the large end of NIH funding for individual biomedical efforts. The typical NIH research grant ranges from $100 thousand to $2 million, and anything bigger is fodder for university news releases. Which raises the question: what have US taxpayers gotten in return?

I ask this as a patient who is grateful that these scientists are working to understand a disease that affects me, my family, and millions in the US and worldwide.

The answer is not obvious, since the publications page on the ADRN website hasn’t been updated since July 2011.

According to the website:
The Atopic Dermatitis Research Network (ADRN) is a consortium of academic medical centers that will conduct clinical research studies in an attempt to learn more about skin infections associated with atopic dermatitis (AD). The studies will focus on antibiotic-resistant Staphylococcus aureus infections and widespread viral infections of the skin, both of which are more prevalent among AD patients. The ADRN will build on the work of the Atopic Dermatitis and Vaccinia Network (ADVN) which conducted clinical studies focused on making smallpox vaccinations safer for people with AD. 
This research will lead to a greater understanding of the immune system in AD patients and may lead to novel therapeutic strategies to manage or prevent infectious complications associated with this disease. 
The ADRN will conduct a number of clinical studies over the next five years and will be enrolling large numbers of people with AD.
A search on returns two entries for the ADRN: one (open) to create a database of patients for the study of genetic markers connected to susceptibility to infections, and one (completed) to look into how AD patients respond to a new flu vaccine.

The ADRN’s NIH contract number is HHSN272201000020C. A search in the NIH’s PubMed database returns 12 papers that acknowledge funding by that contract number. Three of those are review papers (which did not involve new research).

So that makes  two clinical trials and nine research papers, three years into a five-year $42 million project.

Should US taxpayers expect more; be satisfied; or be impressed?

The answer is probably that we will have to wait to find out.

In each year, a typical top university research lab operates on about $2-3M a year and publishes somewhere around ten papers. That’s roughly $200k a paper.

Three of the five years in the ADRN contract are up; three-fifths of $42M is around $24M. We might therefore naively estimate that we should have seen upwards of 100 papers produced so far.

Most likely the reasons there are only 12 at the moment are that you don't start publishing papers right at the outset of a project. The research must be done first and then written up; and the process of getting accepted to a journal takes months. And the ADRN appears largely to rely on clinical trials--which take time to set up.

So why do we only see two trials listed on

I've never had anything to do with a clinical trial, but when I was a researcher, I conducted animal experiments, and there were formidable administrative hurdles to get over before I could start work. I imagine that trials with human subjects are heavily regulated by the government, and for good reason. So the apparently small output of the ADRN to date is, I'm guessing, because it takes a long time to plan trials, get approval, and conduct them, before you can begin analyzing data and reporting it.
Still, let's keep in mind that the ADRN is an extension of the ADVN. It’s not like the ADRN began from scratch—the scientists had the momentum of existing expertise and administration and research aims.

Looking at the titles of the published papers, I can't immediately judge which are the most important. So I emailed Donald Leung, the principal investigator for the ADRN (he's a professor and head of the Division of Pediatric Allergy and Immunology at National Jewish Health), and asked him whether he could summarize the consortium’s findings so far and highlight key points. I hope to hear back from him soon and perhaps to interview him on the phone.

I’d like to know what ADRN scientists have found that surprises them. What have they learned that is truly new?

And what is going to be truly useful to patients in the end? Publishing papers should not be the be-all and end-all of scientific research. What about patents? I’d like to know whether anyone in the ADRN has thought about controlling intellectual property and commercialization. While it’s true that clinical studies may highlight the ideal dosing amount or schedule for existing therapies, and this does not involve creating a new commercial enterprise, most medical technology must pass through the marketplace before it can benefit the consumer/patient.

Someone has to do the dirty work of developing scientific discovery into therapy, and it’s not academic scientists.

More to come.

Tuesday, June 18, 2013

Supreme Court gene patent decision means little for eczema research

Following last week’s decision by the US Supreme Court that human genes cannot be patented, I’d say nothing has changed for eczema patients.

What I mean is that it makes little difference to eczema therapies now or in the future whether companies can obtain US patents on human genes.

I see two major issues: moral and commercial. Morally, I feel it’s a great triumph that even the famously conservative justices of the Supreme Court—who we really expected to side with big bucks, as they seem reliably to do—unanimously affirmed that nobody can own naturally-occurring human DNA. No company can own a piece of my genetic heritage.

Commercially, the issue is intellectual property. I work in biotech, and every day I hear about how it’s crucial for companies to control their IP. No investor is going to back a company that can obviously be sued in the future or that is developing a product that could instantly be copied by a competitor without penalty.

The loser in the decision was Myriad Genetics, which owned the US patent on BRCA1 and BRCA2, two human genes in which mutations increase one’s chances of getting breast cancer. (From what I can tell, Myriad had patents on the normal genes as well as common cancer-linked mutations.) Myriad had exclusive rights to DNA tests that could determine whether patients had mutations. Now many other companies are developing similar tests, and the competition will drive down the price of the tests.

That’s great if you want to get tested for breast cancer. But what does it mean for companies that are developing diagnostic tests for other conditions? These companies may abandon their efforts. Or the companies may never get started.

At least that is what one commercially-minded person whose views I respect tells me.

The Faster Cures blog, conversely, makes the point that patenting DNA could, and has, led to R&D on diseases being blocked by legal obstruction. Lilly, apparently, spent eight years fighting Harvard, MIT and others over the rights to one particular gene, NF-kB. Presumably lots of money got spent that might have gone to actual research instead of lawyers.

But for a gene patent to be useful, there must first of all be a strong link between genetics and disease. Eczema, despite being known to have a strong genetic component, has not been definitively linked to genes except in the case of filaggrin. There are a few mutations that seem to correspond to particularly severe eczema but they don’t occur in many people.

In any case, the sequence of filaggrin was made public in 2006 so the point is moot—once made public, an invention can’t be patented. (I searched the US Patent and Trademark Office database and didn’t see anything.)

Also a diagnostic test is only useful if it gives you information you can act on. There’s no point telling an adult that they have severe eczema, because they already know that. And if parents learn that their child is at risk—not guaranteed—of developing eczema, what can they do to prevent it?

Not much that I know of.

Diagnostics aside, how might a gene patent be useful?

Many drugs or biotherapies being developed affect how genes are regulated—how the process of turning their information into protein is amplified or damped. Perhaps owning a gene patent would let you control work that other people are doing to regulate that gene. We’ll never know now! What is certain, though, is that if you had a gene patent and lots of money, you could probably intimidate other companies by threatening them with expensive legal action.

I don’t think enough is known about eczema at this point that a gene patent would have been a factor. Look at the existing therapies and the few in the pipeline (such as Anacor’s). They are all either anti-inflammatories or calcineurin inhibitors. They don’t affect genes directly.

Researchers are starting to put together useful models of how itch signals get transmitted from the skin to the brain. For itch, we wouldn’t be interested in a diagnostic, but we would like to have a therapy. It’s conceivable that one or two genes may turn out to be key, and we might want drugs to regulate them. But gene patents would not be necessary for scientists or companies to do that work.

In short: last week’s Supreme Court decision, while morally important and laudable, will have little effect on the field of eczema research and therapy.

Wednesday, June 12, 2013

Scientists identify two classes of itch neuron by turning them off separately

For several years it’s been known that itch and pain signals from the skin are carried by different types of neuron to the spinal cord and brain. But there's more than one kind of itch. Scientists have now clearly identified at least two types of itch neuron—one that responds to histamine and a second type that responds to other itch-provoking molecules.

These results could lead to drugs that selectively shut down chronic itch in eczema patients but leave the rest of the sensory system intact.

Some itch is caused by histamine, which triggers an itch signal in certain neurons. But histamine is not the main source of itch for eczema patients. In eczema, most itch has its origins in allergy, when mast cells release “pruritogens” that bind to receptors on itch neurons.

For a long time it was an open question whether histamine and the other pruritogens were triggering itch signals in the same neurons, or different types that scientists could distinguish experimentally.

In late May, researchers led by Alexander Binshtok at the Hebrew University in Jerusalem and Clifford Woolf at Harvard Medical School reported results that clearly showed histamine and non-histamine itch signals are carried by different neurons. The research was published in the journal Nature Neuroscience.

The scientists used a novel two-stage experimental technique to shut the two neuron types down independently. Perhaps someday a similar technique might be embodied in an anti-itch therapy.

What they did was to exploit the fact that when neurons detect histamine and pruritogens, large-diameter channels open in the neurons to let in ions (charged particles) that initiate the electrochemical itch signal, which relies on sodium and potassium.

First, the scientists treated mice with either histamine or a non-histamine pruritogen. At the same time they injected the mice with QX-314, a molecule that blocks sodium ion channels (which are very small-diameter). The large-bore ion channels opened to let in sodium, potassium, and QX-314.

Thereafter, those neurons were unable to fire itch signals, because their sodium channels were blocked by QX-314. The scientists showed that when they dosed the mice with histamine and QX-314, one group of neurons didn’t work (and the mice didn't scratch). When they dosed the mice with other pruritogens and QX-314, the histamine itch neurons worked, but other subsets of neurons were shut off (and the mice didn't scratch).

The scientists’ technique is not directly translatable to therapy, because this study was conducted in mice and involved injection, which is not practical for daily use. But the molecular action they were studying takes place in the upper skin layers, and one could imagine that someday a cream or ointment might be developed that would include two components: one to open large-bore ion channels that detect pruritogens, and another to block the electrochemical signals in those neurons.

Hat tip to Ryan.

PS in a recent post I discussed the difference between TRPV1 ion channels, required for histamine itch, and TRPA1 channels, required for chronic itch. These are the "large-bore" channels mentioned above. Trivia: To trigger a histamine itch signal in a neuron, histamine must activate both TRPV1 and the H1 histamine receptor. To trigger a non-histamine itch signal in a neuron, a pruritogen must activate both TRPA1 and a special pruritogen receptor--"MrgprC11" in the case of dry skin.

Friday, June 7, 2013

Daughter is allergic to sesame, horses. Horses!?

Unfortunately medicine is still far from the Star Trek tricorder stage, at which you can just wave your iPhone over someone and tell what they’re allergic to, but the next best thing is specific IgE testing. We got my daughter V’s results back today. I found the process and fascinating and the outcome illuminating.

IgE are the antibodies responsible for allergy. The IgE results we got consisted of an antibody quantity in units/ml (whatever “units” are), plus a “class” (from 0 to VI) which indicates the degree of allergy. Class can range from “negative” to “extremely high positive.”

Now, I need to talk to an allergist to figure out what is meant by “class”. It seems to be a value that a clinician makes a guess at based on the IgE measurement and the patient’s medical history and, possibly, the allergen in question. From what I can tell the class reported can vary depending on the assay and the person doing the estimating.

The results:

V  is apparently moderately allergic to peanut (3.7 U/ml, class III) and almond (2.5 U/ml, class II) so tree nuts are still out.

She’s allergic to milk (8.3 U/ml, class III), which we know all too well, since only last week I gave her milk by accident and she spent the next half hour barfing on the kitchen floor.

Quite a surprise to find out was that her highest antibody level is to sesame (14.7 U/ml, class III). I once gave her sesame sticks once and she vomited. I gave her a sesame bagel and she said her stomach hurt. But she’s been happily eating pressed sheets of nori (seaweed) that apparently contain sesame oil. Anyway, from now on: no sesame!

And here’s the funny thing. Along with her brother, she gets horse-riding lessons every two weeks. She comes back from them all blotchy in the face. We thought it might be from grass pollen, but on a whim my wife had her tested for allergy to “horse dander.” And she tested positive (3.4 U/ml, class II)!

But no allergy to rye grass pollen.

Allergic to horses. Who knew. Well, that ought to be an easy one to avoid. And it’ll give me a great excuse when she starts demanding a pony for her birthday.

Thursday, June 6, 2013

Allergy testing reminds me how little I know about medicine

Yesterday my daughter V went in for what has become a yearly ritual: her specific IgE blood test. She bravely went in after listening to the previous patient scream for 20 minutes. She yelped when she was stuck, but gritted it out while the nurse drew four vials of blood.

Four vials seems like a lot. My wife, who is a veterinarian, says she only takes one vial to test dogs for multiple allergens.

The process reminds me how little I know about medicine in practice.

IgE is a type of antibody, a Y-shaped molecule with sticky ends that recognizes allergens and triggers inflammation. Kaiser Permanente, our HMO, uses the ELISA test to measure IgE levels, instead of RAST, which has been abandoned since 2010 because it involves using radioactive material.

The first result came back as “IgE, QN    368    Standard range 0 - 75    U/mL”

"U" is for "unit." How many antibodies in a unit? I have no idea. The internet is no help here. 368 U/ml, from what I can tell, is her measure of total IgE, all the antibodies of this type she has circulating in her blood.

So that means V's IgE is five times the maximum normal limit. That’s typical for someone with atopy.

We’re still waiting for the specific results. I wouldn’t put it past Kaiser to waste at least one vial doing the wrong test, and then tell us we need to come in and give more blood.

Last year, among other things, V tested positive for IgE against milk, with 7.8 U/mL. I find it remarkable that her titer of antibodies to milk is 10% of the maximum number of antibodies that a “normal” person should have against everything.

V has eczema and mild asthma. Positive IgE tests are no guarantee of allergy, but we know she’s allergic to milk, since she vomits every time we give it to her. (Our son has no allergies and my wife and I have accidentally switched the kids’ glasses at lunch. Oops.)

She also has consistently tested positive for peanut and walnut allergy (and beef!), though there are as yet no incidents where she’s eaten some and had a reaction. We’re just trying to keep tabs on her allergies as she grows up, hoping, of course, that they will go away—but also fearing that she could develop a life-threatening allergy.

Tuesday, June 4, 2013

Key to chronic eczema itch may lie in special ion channel

Recently scientists reported the discovery of an “itch molecule” (Nppb)  responsible for conveying the itch signal across the synapse from sensory neurons in the skin to neurons in the dorsal horn of the spinal cord.

The media made a great deal of this study, which laid out a substantial model for how we feel itch.

Something I hadn’t noticed, though, was that the Science study considered only a subset of neurons involved in sensing itch—those that are activated by histamine. These neurons, at the itch-sensing end, have a type of ion channel called “TRPV1” that detects histamine and other substances, or “pruritogens,” that induce itch.

An ion channel is a kind of gate that opens when a key--such as a histamine molecule--binds to it. The open gate lets in sodium or potassium ions. When this happens to ion channels in a neuron, the neuron sends an electrical pulse down its length, transmitting information, such as a sensation of itch.

But there are other triggers for itch besides histamine. “Histamine-independent” itch is particularly important in the chronic itch experienced by eczema patients. (And that's why antihistamines don't do us any good.)

Histamine-independent itch is transmitted by neurons that possess TRPA1 ion channels. A new study, published in the Journal of Neuroscience, shows that mice only feel chronic itch if they have neurons expressing TRPA1 channels. Strikingly, the scientists show that knocking out TRPV1 channels (the histamine-dependent kind) does not affect the ability of mice to feel chronic itch.

As a model of chronic itch, the researchers shaved the cheeks of lab mice and exposed the skin to drying chemicals over a period of a few days. The mice scratched their cheeks and developed classic signs of dry, itchy skin--unless their TRPA1 channels had either been genetically deleted or inhibited by a drug,in which cases they hardly scratched at all.

The researchers were also interested in whether the itch-scratch cycle affected the sensation of itch. If you don’t scratch an itch, does it get better or worse? The answer appears to be that if you (or, by proxy, a lab mouse) have an itch on your back that you can only scratch by rubbing it against the wall, it may torment you, but when measured by objective standards, skin that you don’t scratch ends up in better shape.

We can draw two practical conclusions from this work, which was led by Diana Bautista at UC Berkeley: that blocking TRPA1 channels with a drug in cream or ointment form could be a potential solution to the chronic itch of eczema; and that it really does appear that if you can break the itch-scratch cycle, your skin will be better off.

Now, we all know how difficult it is to stop scratching. It’s not as easy as saying that you’ll stop. But this type of research certainly highlights the positive feedback of habit-reversal, which uses psychiatric techniques to reduce habitual scratching. Scratch less…and you’ll feel less itchy.

I do have one question: does the molecule Nppb, reported in the Science paper two weeks ago, transmit chronic itch signals as well as histamine-induced itch? If so, it is still a valuable target for further research into eczema therapies.