Tuesday, July 31, 2012

Benign bacteria help T cells signal skin infection

Benign bacteria on our skin partner with T cells to alert the immune system to the presence of dangerous pathogens, according to research recently published online in the journal Science.

The NIH press release explains the science very well, probably better than I could, so I have copied their text below.

The most relevant point that I can see is that this work shows that microbes living on healthy skin have an important role in our immune system. It's a philosophical question whether the microbes are separate from us--or are part of us, even though they don't share our DNA. If you overuse antibiotic ointments (that is, apply them for periods longer than required to treat an infection), you are killing off helpful microbes and weakening your immune response.
NIH team describes protective role of skin microbiota
Commensal bacteria and immune cells work together to fight harmful microbes

WHAT: A research team at the National Institutes of Health has found that bacteria that normally live in the skin may help protect the body from infection. As the largest organ of the body, the skin represents a major site of interaction with microbes in the environment.

Although immune cells in the skin protect against harmful organisms, until now, it has not been known if the millions of naturally occurring commensal bacteria in the skin—collectively known as the skin microbiota—also have a beneficial role. Using mouse models, the NIH team observed that commensals contribute to protective immunity by interacting with the immune cells in the skin. Their findings appear online on July 26th in Science.

The investigators colonized germ-free mice (mice bred with no naturally occurring microbes in the gut or skin) with the human skin commensal Staphylococcus epidermidis. The team observed that colonizing the mice with this one species of good bacteria enabled an immune cell in the mouse skin to produce a cell-signaling molecule needed to protect against harmful microbes. The researchers subsequently infected both colonized and non-colonized germ-free mice with a parasite. Mice that were not colonized with the bacteria did not mount an effective immune response to the parasite; mice that were colonized did.

In separate experiments, the team sought to determine if the presence or absence of commensals in the gut played a role in skin immunity. They observed that adding or eliminating beneficial bacteria in the gut did not affect the immune response at the skin. These findings indicate that microbiota found in different tissues—skin, gut, lung—have unique roles at each site and that maintaining good health requires the presence of several different sets of commensal communities.

This study provides new insights into the protective role of skin commensals, and demonstrates that skin health relies on the interaction of commensals and immune cells. Further research is needed, say the authors, to determine whether skin disorders such as eczema and psoriasis may be caused or exacerbated by an imbalance of skin commensals and potentially harmful microbes that influence the skin and its immune cells.

Tuesday, July 24, 2012

"Red skin syndrome" hyped, but real

A while ago I got a news alert linking to a disturbing press release claiming that topical steroids, commonly prescribed to treat eczema, were in some cases intensifying disease symptoms.

From the release:
Using mild over-the-counter hydro-cortisone creams to a range of prescription steroid creams, one's skin can become addicted in less than two weeks of usage and develop worsening symptoms that appear to the [sic] be simply spreading Eczema. However the problem is worsening from the medication.
Press releases usually contain news. So what is news here? The release was published by a 501 (c) (3) nonprofit called “The International Topical Steroid Addiction Network,” founded by a dermatologist, Marvin Rapaport, and Kelly Palace, a former patient of Rapaport's. Rapaport practices in Beverly Hills, California.

It's not news that strong steroids are bad for you. But I hadn’t heard of the phenomenon described by ITSAN before. As I always do when I hear of unfamiliar scientific or medical concepts, I turned to PubMed, the NIH’s database of published papers. I performed searches for "topical steroid addiction," "corticosteroid addiction," and "steroid addiction." In my experience, well-established concepts leap out of PubMed with thousands of hits.

Topical steroid addiction just barely surfaced above the noise at first. It’s hard to find, but it’s there—in three papers by Rapaport. 

But then, as I dug around, more results began to appear. The problem is that the papers all use different words to describe the central condition, which (on the face at least) is most precisely labeled “steroid-induced rosacealike dermatitis,” commonly called “red skin syndrome.” A review for practicing physicians can be found here.

The first case of red skin syndrome was reported in 1957. So “topical steroid addiction,” as described by ITSAN, is a real, if not new, condition. I don’t know how many patients it affects, but according to some PubMed results I found, it is well-known in India and China, where it may be emerging because stronger steroids are now being more widely prescribed--and perhaps more casually used.

In my opinion ITSAN’s site is garish and alarmist (do they really need that banner image of a crying girl?) and their focus on Rapaport comes across as promotional. In the "About Us" section, they ask:
Could the reason for this huge increase [in the incidence of eczema in the West over the past 30 years] be the use of topical steroids causing Steroid Induced (spreading) Eczema, an iatrogenic (adj.where a medical treatment causes a condition) skin disease?
In a word: no. But the information on the FAQ section of their site looks useful. If you think topical steroids are your biggest problem, then why not stop cold turkey and see if you experience the flareup and cooldown that seem to be typical of addiction?

Friday, July 20, 2012

Will we see gene therapy for eczema?

The European Commission is close to approving the first gene therapy in the Western world, according to the New York Times.

The treatment, called Glybera and developed by the Dutch company uniQure, treats a rare condition in which people are unable to break down fat-carrying molecules.

Gene therapy is one way that I imagine patients of the future might be cured of eczema. Glybera gives us a peek into how that might happen.

In gene therapy, doctors replace a patient’s faulty gene with a good one. The large protein filaggrin is currently the best candidate for eczema gene therapy. Several studies have linked filaggrin mutations to a higher risk of developing eczema.

Filaggrin gene therapy would have to be applied early in life. This is because in our current understanding, eczema is caused by a skin barrier defect that allows allergies to develop after a critical time window. Filaggrin mutations cause a faulty skin barrier. So you’d have to fix filaggrin early, because waiting too long would allow allergies to develop, after which fixing filaggrin solves only half the problem.

Glybera is a biotherapeutic, a gene (length of DNA) that is attached to a well-characterized and benign virus. Doctors will inject Glybera into leg muscles, where the virus infects cells and incorporates itself and the therapeutic gene into the patient's DNA—but only in leg muscle cells, presumably because Glybera gets absorbed locally. Then the patients will be able to break down the fat-carrying molecules, and their blood will no longer be overloaded with fat.

A biotherapeutic for eczema would likely be an intact filaggrin gene incorporated into a similar virus.

Gene therapy for the skin would have to be restricted to skin cells. You could accomplish this with a topical cream or ointment applied in the clinic. I'm guessing you would want to treat your whole skin, not just spots that were flaring up at the time.

How long will it last? The effects of Glybera apparently last for years, probably because muscle cells live a long time. Skin cells are a different matter—they are turning over continually. This could turn out to make gene therapy for skin conditions near-impossible.

But perhaps you could take regular doses—pills or injections—of a gene therapy that includes a genetic switch that turns on only in skin cells.

The critical early window for developing allergies in eczema patients could turn out to be a bonus in disguise. Maybe filaggrin gene therapy would only be required during a window of a few years, after which it could be discontinued and allergies would never develop.

Obviously extensive clinical trials for safety would be necessary. I could imagine this type of therapy becoming available within two decades. My grandchildren could be among the first to benefit.

Thursday, July 19, 2012

The NEA should join Faster Cures nonprofit group

Unless you live under a rock, you’ve probably heard of the Michael J. Fox Foundation for Parkinson’s Research. Fox, the "Back to the Future" etc. megastar who developed early onset Parkinson’s disease, created the foundation to back research leading to a cure.

The Michael J. Fox Foundation is only one of many members of The Research Acceleration and Innovation Network (TRAIN). TRAIN is a child of Faster Cures, the nonprofit patient advocacy organization based in Washington, DC.

Look at the list of TRAIN member organizations. Isn’t it amazing how many diseases there are for which we need scientists and entrepreneurs to develop cures?  But I don’t see the National Eczema Association on the list. I think the NEA should join TRAIN.

Although most of the diseases represented on the member list are terminal or degenerative, and eczema is neither, those of us who suffer from it can attest that it seriously affects, and in the worst cases ruins, our quality of life.

According to the Faster Cures website,
[TRAIN] was established to create opportunities for medical research innovators to discuss and tackle the challenges that cut across diseases. It is a group of unique nonprofit foundations that fund medical research across a spectrum of diseases, from breast cancer to Parkinson's disease. In many cases TRAIN's member foundations have been created by patients and their families who are frustrated by the slow pace of change in the traditional medical research system. They represent the kind of organizations that are fast becoming the engine behind innovation in disease research--collaborative, mission-driven, strategic in their allocation of resources, and results-oriented. They are organizations that have a singular focus on, and a significant stake in, getting promising therapies from the laboratory bench to the patient's bedside as rapidly as possible.
There’s no reason that I can see that the NEA shouldn’t be part of TRAIN. It looks easy to join. What would it get us? From what I can see, TRAIN provides good models for how to set up sponsored research programs, preclinical and clinical trial templates, agreements for how to share biological samples, etc. I don’t run a patient advocacy organization, so I don’t know firsthand how useful this sort of thing could be, but I imagine that it would be a lot easier to grab a template for a clinical trial than to write one from scratch. 

I read Fox’s biographical book “Always Looking Up,” published in 2009. His optimism is infectious. Read that book. You won’t regret it!

Tuesday, July 17, 2012

Do you have a tattoo?

Last Sunday, people-watching at a park with the family, I remarked to my wife how some people like to get tattoos on their necks or arms. You just can't miss a neck tattoo. It conveys a certain je ne sais quoi. Actually, in California, it conveys that you belong to a gang.

"Why would you get a tattoo?" I asked.

"Well, my sister has a giant eagle tattooed on her back," she said.

I didn't know that. My sister-in-law is a bit of a daredevil, and as she nears 40 with two kids, still enjoys the flying trapeze.

"Yes, she did it in her 20s."

And here I must admit that I did, briefly, in my 20s, consider getting a tattoo. It was during my summer in the Canadian military reserves, at Camp Gagetown, New Brunswick. A bunch of mates and I were off-duty at the Canadian equivalent of the Px, as it was too early to start drinking. One guy pointed out a tattoo parlor. "Hey, let's all get tattoos," he said. There was a folder with art samples you could ask to have permanently inked into your skin. I examined the catalog. It seemed to consist exclusively of logos of heavy-metal bands. Jazz being more my thing, I excused myself to get an icecream cone, while my mate rolled up his sleeve, indicating his preference to display an image of Mötley Crüe's "Dr Feelgood" on his bicep until the day he died.

I wonder whether he still feels good about that decision.

That summer was remarkable for me. My eczema completely cleared up. I suspect it was because, being a trooper, I was ordered around the whole time and never had to make a decision for myself. (I kid you not--on the first day, we spent hours learning how to take one step forward.) No decisions, no stress. The warrant officer could singe my ears blue with profanities, informing me that the way I was shouldering my rifle was far from ideal. It didn't matter. I just marched where I was told.

But even then, with perfect skin, I knew that getting a tattoo would be a bad idea. I think I've had eczema on every square inch of my skin since then. Every square inch. What does eczema do to a tattoo? If you scratch, does the ink get torn up and the picture blotched? I'd think so.

Have you gotten a tattoo?

Wednesday, July 11, 2012

New smallpox vaccine safe for eczema patients

A Danish company will be supplying the US government with 20 million doses of a smallpox vaccine that is safe for eczema patients--unlike the existing vaccine, which can cause rampant and life-threatening infection in rare cases. I blog briefly about it on the National Eczema Association website.

Monday, July 9, 2012

Wheat opens up a whole new universe of food

For the first year of my daughter Voov's life, her face and hands were a red mess of eczema. Blood laced her stool. The combination of symptoms led us and her doctor to think that some allergen was to blame. Skin prick tests registered positive for almost everything--which wasn't much help! Voov was breastfed, so my wife began to cut out foods in her own diet for two weeks at a time to see if anything changed. Removing dairy improved things; so that was it for cow-based milk and ice cream for my wife for a long time.

Then we started Voov on solid foods. At first she had only 12 options, several of which she refused outright. And so most of the atoms now composing her body lived previous lives as chicken, tofu, rice, apple, peas, and banana.

After three years, we redid the skin prick test, and while the technician made a hash of reading the results, we took the apparent improvement as a license to start trying a host of new things. We began with high-value, low-risk items like carrots, potato, chard, and quinoa. It was marvelous: Voov had no reaction to any of them. Eggs, even.

The problem was that she didn't like to eat any of them. She was set in her ways. It seems that three years is precisely the wrong age to start introducing a kid to new foods. However, there was one notable exception: ketchup. We ran trials of tomato and onion, and then Heinz--and bingo, we'd found something she liked and didn't react to.

I immediately realized that I could cover any food in ketchup and there'd be a good chance she'd eat it.

This past week, though, has seen a revolution.

Still standing as major potential villains were the big four: fish, dairy, nuts, and wheat. My wife is a fish-phobe so it's not worth worrying about fish because I can never cook it for the family. We know Voov is allergic to milk, because she threw up shortly after she drank some by accident (her skin test showed major allergy to milk and beef). And we're leaving nuts as something to try in the doctor's office when we have an epi-pen handy. That left one thing to try: wheat.

One week ago, we began giving Voov slices of wheat bread (after carefully checking the ingredient list; it's amazing how many breads contain milk products). She loves it, and she loves wheat noodles, and so far she hasn't had the slightest apparent reaction. Awesome! It has opened up a whole new universe of food.

In the space of a few weeks, we've completely inverted our food restrictions. Instead of Voov only being able to eat a few things, she's suddenly able to eat all BUT a few things. We'll be reading ingredient labels for years to come, but our lives have gotten much simpler and easier.

Coincidentally, Selena over at Amazing & Atopic started her daughter on wheat this week. Things didn't go so well for her, unfortunately.

Thursday, July 5, 2012

Antibody therapy appears powerful against psoriasis

A biotechnology therapeutic for psoriasis appears to clear most of the symptoms in many patients, according to recently published results of clinical trials.

The therapeutic is “ixekizumab,” an antibody that inactivates a “cytokine” or signaling molecule produced by a subset of white blood cells called type 17 helper T cells.* Researchers at the pharmaceutical company Eli Lilly and university colleagues published the Phase 2 results in the New England Journal of Medicine in March. I learned about ixekizumab from a JACI paper published last week, reporting on aspects of the earlier Phase 1 trial.

Th17 are thought to be overactive in psoriasis patients. That is not the case in patients with atopic dermatitis, for whom helper T cells of types 2 and 22 generally exist in higher numbers and are more active than they are in the average person. The authors of the JACI paper speculate that tailored antibody therapy could prove as effective in controlling eczema as ixekizumab has for psoriasis.

In the Phase 2 trial, researchers injected 142 patients with various doses of ixekizumab at regular intervals over a 16-week period. They found that, for all but the lowest dosage, the antibody mostly cleared up psoriasis—as measured by a standard set of measures—for more than 75% of the patients in the trial.

The authors did not present data showing how long the effects lasted. But they did note that hardly anyone dropped out of the trial because of adverse effects. (From what I can tell, those who dropped out came from the lowest dosage group.)

Nor was there any indication how expensive ixekizumab might be. I imagine that, compared to drugs such as steroids, custom-produced antibodies would be extremely expensive for patients and insurers.

Nevertheless, the results are unusually positive. A blog post on the JACI website called the results “near-astonishing.” Keeping in mind that all trials and papers published on them are bankrolled by pharma companies (who else can pay for clinical trials?) this area of antibodies against T cell cytokines seems worth watching closely.

* I am pretty sure that Th17 cells are not the seventeenth type of helper T cells. The only ones I've ever heard of are Th1, Th2, Th17, and Th22. I don't know why the last two are numbered 17 and 22 instead of 3 and 4. This sort of thing is why I got out of immunology.

Monday, July 2, 2012

Rochester group to focus on skin barrier

Alice Pentland, chair of the Department of Dermatology at the University of Rochester Medical Center, whom I interviewed recently for a post on the NEA website, also directs the newly-formed Skin Barrier Research Consortium, a subunit of her department. The group, as its name suggests, brings together scientists studying the skin barrier--in particular, its permeability, which is thought to be a key factor in allergic eczema, and which could in normal skin be temporarily increased to administer needle-free vaccines.

I learned about the consortium from a Rochester press release. According to Pentland there is no special funding. They aren't applying for any large NIH grants. So the group's formation is symbolic. But it might give the department a mission, and could make it a more formidable applicant for future grants.

Pentland detailed the roles of the researchers in the consortium for me. Of particular interest to eczema patients:
  • Lisa Beck, who is conducting a pilot-stage clinical trial of Actos, a drug originally developed for diabetics but also found to increase the integrity of the skin. Beck is also building a registry of patients (apparently more than 200 now) who have "classic" (and I'd assume that means "allergic") atopic dermatitis, partly characterized by high levels of IgE antibodies in the blood. A major problem for dermatologists, Pentland said, is that several conditions look like AD on the surface but aren't. A vetted registry of patients will help researchers study causes of AD.
  • Anna De Benedetto, a doctor who is studying how the electrical resistance of skin is correlated with its permeability
  • Ben Miller, a chemist who is synthesizing small drug molecules aimed at targets identified by others in the group
  • Lisa DeLouise, a material scientist looking at how a changed skin barrier, caused by AD or sunburn, may make nanoparticles toxic when they normally wouldn't be
  • and Elaine Gilmore, who studies the molecular mechanisms of itch.
"It's a good broad-spectrum effort," Pentland says of the consortium. I'll be following their work. I'm most excited about the Actos trial, but I look forward to learning about collaborations between members of the group.