Does gluten drive skin disease?

Gluten and gluten-sensitive enteropathy have become hot topics among the lay public and in medical practices. We dermatologists have historically concerned ourselves with gluten only as it relates to dermatitis herpetiformis. This may be changing. John Zone, M.D., from the University of Utah, Salt Lake City, discusses how gluten sensitive enteropathy may impact many areas of our specialty.

Dr. Levine: Exactly what is gluten and what is a gluten-sensitive enteropathy?

A: John Zone, M.D.: Gluten is really a group of proteins that is in various grains: rye, barley and wheat. There are specific substances in them called prolamins that are responsible for the immune response. That group of proteins is not present in rice or oats; it is just present in rye, barley and wheat. These proteins are large enough to produce an immune response, and that’s what they do in celiac disease and possibly in other conditions.

Dr. Levine: So when we talk about gluten-sensitive enteropathy, what does that mean?

A: Gluten-sensitive enteropathy and celiac disease are synonymous. Gluten-sensitive enteropathy means that there is damage to the intestinal mucosa that is induced by gluten, and when gluten is withdrawn from the diet, the damaged mucosa heals over in a matter of months. So that’s gluten-sensitive enteropathy. There, of course, are other enteropathies that aren’t sensitive to gluten.

Dr. Levine: All of a sudden, it seems like people are talking about this and it seems like the incidence of this has become tremendously high. What happened?

A: The first thing that made celiac disease more common was better testing and identification of occult disease.

I started studying celiac disease and gluten sensitivity back in the 1970s, and it was deemed to be very rare. At that time, the only way that people could be diagnosed was with a small intestinal biopsy or with a skin biopsy if they had dermatitis herpetiformis.

We got better blood tests in the 1990s and a lot of work was done on establishing the reliability of various blood tests in predicting the intestinal abnormality. So with the availability of a blood test, it was first found in about 2000 that about one in 100 people in the United States had a positive blood test for celiac disease, and if you go ahead and biopsy their intestine, you will find out that indeed they have gluten-sensitive enteropathy or celiac disease of the intestine.

We used to think that people only had celiac disease if they had a lot of symptoms: crampy abdominal pain, diarrhea, etc. Now we know from our blood test that up to two-thirds of the people do not have abdominal symptoms, but they may have secondary complications such as malabsorption of iron and osteoporosis.

The question of whether or not the incidence of celiac disease is actually increasing with time is an interesting one. There is only one study that I know of that actually has dealt with that.

Joseph Murray, M.D., a researcher at Mayo Clinic, took serum that had been stored since the 1960s or ’50s, I am not sure, for military recruit and established their serum positivity. It was much lower than a comparable group today. It may well be that the incidence of celiac disease and gluten sensitivity is increasing for reasons other than better testing, we don’t know what those reasons might be (Murray JA, Van Dyke C, Plevak MF, et al. Clin Gastroenterol Hepatol. 2003;1(1):19-27).

Dr. Levine: Could it have anything to do with our diet and how it changed over time?

A: In the long run, yes. Prior to 10,000 years ago, and then grain was a relatively new thing in the human diet 5,000 years ago or thereabouts. That change in diet over time - where men started to eat more grain - has likely produced a population that reacts to dietary gluten. As far as change in diet in the past 20 years, there is no evidence that I am aware of that this has been a factor. Some people have considered the possibility that gluten sensitivity has been increased by viral infections and other things that have precipitated it, but no one knows the answer.

Dr. Levine: Let’s move on to the disease that all of us grew up thinking about in relation to gluten, and that is dermatitis herpetiformis. Has the incidence of this disease changed over the past 30 to 40 years?

A: The only incidence study done in the United States, we did in Utah in 1987, and we haven’t repeated the incidence study. To me, it seems about the same as it has always been: approximately 11 new cases per 100,000 population per year. (Smith JB, Tulloch JE, Meyer LJ, Zone JJ. Arch Dermatol. 1992;128(12):1608-1610). Those numbers have ranged as low as three or four and as high as 12 in different reports, but there doesn’t seem to be any difference.

Dr. Levine: Why are there so few cases of dermatitis herpetiformis while so many people have gluten sensitivity?

A: Well it’s interesting, because in Finland, Timo Reunala, M.D., at the University of Tampere, Finland, who is a colleague, has been investigating this for many years. In a large population study, he found that one out of every six patients with celiac disease had dermatitis herpetiformis (Salmi TT, Hervonen K, Kautiainen H, Collin P, Reunala T. Br J Dermatol. 2011;165(2):354-359). That’s relatively common. Most of these people when they were diagnosed with celiac disease went on a gluten-free diet and their dermatitis cleared relatively rapidly. So the incidence of dermatitis herpetiformis is much higher than we think. When one really goes after it, you will find a reasonable number of new cases. But I think today, a lot of them are rapidly treated with gluten-free diet.

Plus an interesting thing has happened in society now, of course, and that is that 20 years ago gluten restriction was not very popular, but it has become almost a fad now. So you can go to any restaurant and get a gluten-free diet. I see patients all the time who have had dermatitis herpetiformis, who will say, “Oh yeah, I figured that it was related to celiac disease and I went on a gluten-free diet.” For every one of those, there are probably 10 other people who had gone on gluten-free diets for no particular reason and have not gotten better, but a gluten-free diet has become very popular.

Dr. Levine: Is that your treatment of choice for dermatitis herpetiformis?

A: Yes. I think the best treatment for dermatitis herpetiformis is a gluten-free diet. Traditionally when we were started in dermatology, we treated everyone with dapsone. Dapsone, if the patient tolerates it, clears the skin and suppresses the disease. However, dermatitis herpetiformis recurs if a regular diet is instituted again. If managed correctly in the right doses, it will suppress the disease indefinitely.

I just had a patient of mine pass away who had been on dapsone since 1943 and tolerated it pretty well. Now what we do know from some recent studies from Hungary, about 60 percent of the people have osteoporosis because of malabsorption - and they are subject to other malabsorptive problems also. (Sárdy M, Kárpáti S, Merkl B, et al. J Exp Med. 2002;195(6):747-757). So, gluten-free diet is probably the best treatment since it may ultimately reduce the incidence of osteopenia.

What I do now is start patients on a gluten-free diet and a small dose of dapsone to make them comfortable and then gradually try to taper their dapsone and maintain them on a gluten-free diet. Of course there are number of people who just once they find out how well dapsone works, don’t want any part of a gluten-free diet, and I just explain to them that they are at an increased risk for osteoporosis and possibly secondary lymphoma.

Dr. Levine: How do you specifically guide them in terms of avoiding gluten?

A: I used to have a detailed handout that I had made with a dietitian, and I used to refer them to dietitians. With the Internet now, I tell them particular Internet sites and organizations that I know have good quality information. In our region, I used the Celiac Disease Foundation of Los Angeles that I work with, and I know that its information is first-class - or the Gluten Intolerance Group of Seattle. All the information is online. There is also the advantage that many of the patients become part of the self-help groups of these organizations and stay much more current on the details of the diet than I do, actually.

Dr. Levine: Let’s move on to other possible associations of a gluten-sensitive enteropathy and other dermatoses that have been proposed to be related to celiac disease. Could you address the association of psoriasis and gluten sensitivity?

A: There are multiple diseases that have been said to be associated with gluten sensitivity. It appears that when people have celiac disease, they have a heightened immune response. They are very flared up from an immunologic standpoint. If a person with celiac disease happens to have psoriasis, - both of those diseases are fairly common; so if one in 100 people has celiac disease and one in 100 people has psoriasis, you can imagine that a number of people have both diseases.

Those people who have both diseases have been reported repeatedly to improve their psoriasis on a gluten-free diet; however, because the coexistence of the two is relatively rare, we don’t routinely test psoriatics for celiac disease. Those papers have come mostly from Sweden, where, of course, they have a much better control of their population and can document associations easily in the population In the United States, we don’t have the population studies available.

Dr. Levine: Is there a situation where you would ever take a person with psoriasis and somehow determine whether they have gluten-sensitive enteropathy?

A: Gluten-sensitive enteropathy, of course, is familial. In our studies of 2,000 first-degree relatives, we found that one in eight (12 percent) of the first-degree relatives of celiac patients turned out to have celiac disease. So if a person with psoriasis had a family history of celiac disease, I would definitely test that person for celiac disease. If they didn’t have a family history of celiac disease, then there is a one in 100 chance that a psoriatic has celiac disease. I am not saying that psoriasis is caused by celiac disease in selected cases.

Dr. Levine: In like fashion, the controversy of atopic dermatitis and any kind of dietary issues have been raised in the literature; what’s your view of atopic dermatitis and gluten-sensitive enteropathy?

A: Luigi Greco, M.D., at the University of Naples Federico II, Naples, Italy, has looked into this in detail and the story is the same. The incidence of celiac disease was not higher in those with atopic dermatitis. It’s still just 1 in 100. So 1 in 100 patients with atopic dermatitis will have celiac disease, just like 1 in 100 Caucasians will have celiac disease.

If that particular person has celiac disease, his/her atopic dermatitis will likely improve on a gluten-free diet. It’s a relatively rare event, but when there is coexistence of the two diseases, once again this hyperactive immune state that is produced by celiac disease or gluten-sensitive enteropathy seems to act as a stimulant. Indeed, I have treated several patients who had hand dermatitis - what we all would have considered atopic dermatitis in adults, at least that’s what I have called them - and turned out to have celiac disease and totally cleared on a gluten-free diet.

I have had people from around the country contact me about such cases, and it does happen. They are relatively rare. On the other hand, somewhere around 5 percent of patients with aphthous stomatitis in adulthood has celiac disease. So if patients who have aphthous stomatitis also have occult celiac disease, the mouth lesions likely will respond to gluten restriction.  That’s what is called non-celiac gluten sensitivity. We are seeing a phenomenon especially in United States where up to 5 percent of the population is saying that they are gluten sensitive. Now we know that the incidence of celiac disease is 1 percent when we really go after people. That means that four out of five people who claim they are been gluten sensitive don’t have celiac disease.

There is an interesting literature developing on non-celiac gluten sensitivity, which is called NCGS in the literature. We usually start out by testing them for celiac disease, we tell them they don’t have celiac disease, but they say, “No, no, I am gluten sensitive.”

Indeed, in some blinded studies, they have been able to show that some of these people will get symptoms when given gluten as opposed to placebo. That’s probably right now the most controversial area in gluten sensitivity. The thing that I ask myself is do the people who have non-celiac gluten sensitivity have skin disease that is driven by gluten, and the answer is we really don’t know. The problem with non-celiac gluten sensitivity is we have no good test for it, so we can’t separate the people who really do have gluten sensitive disease from the people who don’t have gluten sensitive disease other than by blinded challenge.

Dr. Levine: It’s very difficult when so many people claim to have issues with gluten and when one questions them, it sounds less likely. How many frogs do you kiss before you get to your prince. I tend to dismiss all of them and what are you saying is maybe that is not the right approach.

A: The tendency is to dismiss them and the bigger problem is that by the time we get to see them, they are frequently already on a gluten-free diet. Just in my regular dermatology clinic, we see people coming in all the time who say they are on a gluten-free diet. Well, a gluten-free diet makes the blood testing for celiac disease negative, so once they come in, I have no way of being able to tell if they have it. It’s very difficult to separate the “wheat from the chaff” if you will, and at this time, we have no reliable way to tell, especially in those people who have been a strict gluten-free diet. DT