2013年6月26日水曜日

About Strong Neo-Minophagen C(SNMC)

Note; This article is a supplementation to the comment in the following article.
[Paradoxical idea of systemic steroids use for withdrawal from topical steroids]
http://mototsugufukaya.blogspot.jp/2013/06/paradoxical-idea-of-systemic-steroids.html
 
Strong Neo-Minophagen C(SNMC) is an old medicine made in Japan. It is administered only by intravenous injection.

The active ingredient is glycyrrhetinic acid, a constituent of liquorice.


The efficacy of Chinese herbs containing liquorice is thought to be due to glycyrrhetinic acid at least partially.

Some doctors in Japan prefer SNMC for suppressing rebound after TSW. The mechanism is considered as 11 beta-OHSD suppression.  11 beta-OHSD is an enzyme  which changes cortisol to cortisone: inactive form of cortisol.



The below graph is from Greaves’s article. The horizontal axis is the concentration of medicines and longitudinal axis is human skin branching due to topical steroids.

Beclomethasone dipropionate and hydrocortisone acetate are both TC and the former is stronger than the latter. The data tells the effect of hydorocortisone acetate is amplified by the addition of glycyrrhetinic acid.

Potentiation of hydrocortisone activity in skin by glycerrhetinic acid. Greaves MW. Lancet. 1990 Oct 6;336(8719):876.

Doctors using SNMC for the rebound seem to consider it is safe because it is not an administration of extrinsic steroids. However, it is very near to the weak systemic steroids injection in fact.

I also have experience of this method. It was rather weak and didn’t become popular among my patients. Systemic steroids injection is more recommendable than SNMC from my thinking but it is certain that SNMC is an alternative method anyway. I have never heard or read that SNMC caused rebound.

SNMC is provided by Minophagen pharmaceutical co. ltd.
http://www.minophagen.co.jp/English/index.html

The product is provided overseas to Asia area.

If any medical doctor who is reading my blog and interested in SNMC, don’t hesitate to contact me. I can export SNMC to your clinic. It is legal under Japanese law. The attached document of SNMC is here (just click).

Or I can export SNMC to any patient who prefer to use SNMC and could find a doctor who would inject it to you in your area. Please contact me by e-mail : fukaya*tclinic.jp (replace *to@).

Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

2013年6月25日火曜日

Is there no need of topical steroids withdrawal if I apply Dr. Fukaya’s lotion?

I received a question from a client of my hyaluronan lotion overseas. A TSA patient who is attending to the online shop in UK diverted it to me.
  
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Thank you for yr kind reply. We are loyal people following Dr Fukaya's blog from XXX, regarding topical steroid withdrawal, addiction.
  
From the online shop, i noticed there is also mention that Dr Fukaya's skin lotion can even be used together with topical steroid? I m curious how this works, because mostly users are trying to stop/wean off steroid completely, resulting in redness, withdrawal symptoms, uncontrollable flares, causing extreme dryness to the skin.

   
But why / how can this skin lotion prevent the side effects of such strong steroid penetration effects? I mean if we continue to use steroid, then why should we be still using Dr Fukaya's lotion? Because steroid will suppress immune system and then there will not be any withdrawal redness etc. So what is the co-relation of these 2?


Can you please enlighten me on this point?

Many thanks in advance.
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I sent the following answer.
  
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The topical steroids have two aspects. They are the immune suppression and the barrier dysfunction (epidermis damage).

My hyaluronic acid suppresses the latter. The mechanism is on the “Why it works?”
http://drfukaya.ocnk.net/page/4.

My hyaluronic acid doesn't suppress the former. The mechanism of TSA is considered as the latter. Please refer to my article “Paradoxical idea of systemic steroids use for withdrawal from topical steroids”
http://mototsugufukaya.blogspot.jp/2013/06/paradoxical-idea-of-systemic-steroids.html
The immune suppression only (systemic steroids) doesn’t cause addiction.
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Soon after that, the mediator herself asked related to the question.

“Doc, I have a question too. Do you think patients who are using TS don’t need withdrawal anymore if they use your hyaluronan lotion ? I mean, does the hyaluronan lotion only decrease the risk of TSA or completely overcome the development of TSA?”

I understood the meaning of the questions of the inquirer and the mediator.
It might be a stress for the patients in the middle of withdrawal from steroids to know there is an agent that decreases or removes the risk of TSA. It will sound a temptation to resume steroids.

But sorry to say, I also don’t know the answer to the question of the mediator yet.

It is certain that my hyaluronan lotion decreases the risk of TSA development of steroid users. Steroid users with hyaluronan lotion should develop less severe rebound even if it occurred. Theoretically the risk disappears completely by using it but I am not sure of it at present.

OK, I say, don’t resume steroids so easily. My hyaluronic acid lotion has only been out for several months so far and it's too early to say my lotion will cease the entire risk of Topical Steroids Addiction. So I would advise to continue TS withdrawal for now.

On the other hands, there must be such patients who are using TS now and can’t stop immediately for various reasons. Use my hyaluronic acid at the same time when you apply TS.

I recommend my hyaluronic acid to the patients also who are not using steroids or stand the hard rebound now. It will help your recovery.

As a conclusion:

1. Don’t change the present stance to TS by knowing the existence of my hyaluronic acid.

2. I would confidently recommend to use my hyaluronic acid lotion to all categories of patients.

3. If you're having financial difficulties (as some people are during TS withdrawal), don't strain yourself. My Hyaluronic acid lotion will be surely beneficial but not absolutely necessary to heal your skin.

That is the honest answer from me. Thank you.
 
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

2013年6月24日月曜日

About house dust mites in the housing environments

Here I will present a case which I saw many years ago.
He suffered from eczema mainly on the lower extremities while there were a few typical lesions of atopic dermatitis also in other parts.
  
His family moved when he was 12 years old. He developed the above described manifestation after that. Their family thought he might have developed TSA because he had used TS so long. So TS was discontinued. But his eczema didn’t subside and worsened every summer. After three years he visited me on Sep 16 1997 (right upper photo).
The rebound due to TSA was excluded from my diagnosis because his skin manifestation differed from it and the seasonal worsening tendency was obvious.

The regular seasonal worsening means he reacted to some environmental factor. So I went to his house for research.

Remember that nobody can correctly identify any environmental aggravating factor without a real field research and any medical doctor including me is not a specialist of such kind of research. So I went to the patient’s house with some specialists. They were architects, pest controllers, chemistry scientists and so on. They were all my friends and I asked them to accompany . I used to repeat such field works more than one hundred times for my patients.

His family lived in a rental apartment. We found the floor was all covered with carpets and our architect judged the house was poor in airflow. Our pest controller collected the dust on the carpets and examined by microscope. The result revealed there were 179.8 house dust mites per square meter and the ratio of male-adult mite, female-adult mite, young mite was 15:5:10. It means the carpets were the place where mites lived and produced descendants.
 

His family moved to the other apartment for the purpose of change of air. We went for the field research again and found the floors were all made of wood and the airflow was enough. The house dust mites on the floor were counted as only one per square meter.

The patient improved rapidly after moving as the top photo in 97.11.20.  I followed him for one subsequent year and confirmed that his eczema never worsened (photo 98.10.23).

I will present another case. She had suffered from the whole body eczema. Her parents stopped TS because they suspected TSA and visited me.


I couldn’t judge her dermatitis was purely of rebound or amplified by the other factor. As her blood examination showed she had high IgE to house dust mites, I went to her house for the research with my comrades.

When we went to her house, she was just sleeping in the sofa. She liked the sofa and slept there every night like the photo. The sofa was made of cloth and we found the density of house dust mites on the sofa was more than 200 per square meter. The sofa must have been absolutely one cause of her eczema.

Remember that we dermatologist can’t know how the environment surrounding an individual patient is like. All people including doctors have a tendency to think their own life-styles as a standard. But in fact all human beings live in the different life styles, that is different environments.

The former dermatologist advised to use allergen-free bed clothing and her parents purchased it. But the parents never suspected the sofa was a nest of house dust mites.
 
The patient recovered gradually after the sofa was discarded. The photo is after one year.
 
I can’t judge how many ratio of the initial eczema was due to TSA and how many ratio was due to the allergy to the house dust mites. However she recovered anyway.

What I’d like to insist is that you could never identify where and how many the house dust mites exist. Look at the below photo for example.

This is a bed of another patient. Can you judge how many mites are on the bed clothing only by seeing it?

On the floor carpet we counted 100/m2, the coverlet 3/m2 and the electric blanket between the coverlet and the bed 650/m2. It is warm and comfortable to use an electric blanket but it is also comfortable for mites.
  
There are other environmental aggravation factors than house dust mites. Most of them are invisible. Only the specialists can identify correctly by the real field research. And such specialists are very rare.

But remember if the factor was identified correctly and removed from your environment, it surely is the most reasonable rescue.

I repeated such works with my comrades who were complete volunteers sympathized for my idea and accompanied with me free of charge. They were all persons of good will.
I am ashamed of myself to my comrades I  couldn't continue the above volunteer work from my personal reason even though I myself was a proposer.

However,there were not so many cases which we could identify the obvious aggravating factors. The rate was less than 10% by my memory. For most patients the housing environment seemed to have no relation with their eczema. But the fact that there was no aggravating factor was of course useful for the patient.

Other aggravating factors in the environment which we could find include mold, formaldehyde in the newly built house and cats. A cat was sometimes identified as an obvious worsening factor visible but difficult to be removed. Most patients didn’t discard their lovely pets and continued to live with cats. I remember one patient. He didn’t use any steroids for many years and his eczema improved soon after admission to our hospital but worsened just after discharge. I went to his house and researched. There was no possible aggravating factor except one cat. But his family couldn’t discard their cat and continued to keep until the death of the cat. After the death of the cat in two years, his eczema completely improved.

What should you do if you suspected the existence of environmental aggravation factor? The most reasonable and scientific way is what I did formerly, that is a real surveillance of your housing environment by specialists. However, you could not find such specialists usually. So I recommend trying a short journey or travel. Especially if you are enough young, you should travel all over the world and look for the environments in which you can live. If I were you, I will definitely do so.

It never means you had better live in the country rich in nature. In fact, allergens are richer in the country than in the city. It is because allergic reaction exists as an offencive reaction against other living things. For a patient with allergy to mold, the safest living space is an apartment on more than the 10th floor in the city. The largest origin producing mold is the soil of the ground.

Your skin itself is an indicator of worsening factors. Utilize it effectively.

I also remember another patient. He suffered from eczema for a long time and I advised him to travel Okinawa, the most southern prefecture in Japan. He became emotional and angry. He appealed that he might die if he traveled at the present skin conditions. I answered “ It would be really nice if one died in such a beautiful place.” So he decided to travel in Okinawa. Just after he got off the airplane he felt comfortable and his skin improved in a few days. He must be living still in Okinawa now.

It is such a thing about the environmental aggravation factors. You, patients with atopic eczema resemble like the sweetfish which live in the clear stream. Try to travel or move drastically and find your place. It might be the best and simple answer.
 
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

2013年6月22日土曜日

Online shop open.

One of TSA patients who is pleased with my hyaluronic acid helped me to create an online shop.
URL is as the following.
http://drfukaya.ocnk.net/

Please refer to the following article about the explanation of my hyaluronic acid.

http://mototsugufukaya.blogspot.jp/2013/06/hyaluronic-acid-of-around-100-thousand.html

I believe it will really help you.
    
June 20, 2013

Mototsugu Fukaya MD,JDA certified dermatologist.

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The photos below are ones taken when I enrolled in ALSO (Advanced Life Support in Obstetrics) with young doctors and nurses two years ago.

I have always felt to be obliged to work for the weakest or the minority of a comunity as a doctor. My participation of ALSO for pregnant women is also from that thinking. I will and want to act as a doctor at any time though I am now retired and a cosmetic surgeon.

And the thought is also the reason why I had seen TSA/TSW patients even though most patients could have been controlled by TS. I preferred to see poorly-controlled patients until their recovery rather than see well-controlled patients.
  

 
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

2013年6月19日水曜日

For parents of the children with atopic dermatitis

Some of my blog readers might be a father or a mother whose child suffers from eczema. They might be puzzled with the problem whether they should use TS or not. Otherwise they might have already decided never to use them.
This blog will not offer any answer to the question. I have never recommended to use or not to use TS because I myself don’t have an obvious answer which is scientifically persuading .
However, if my child were a patient with eczema, I never use TS because I have seen too many patients with TSA. But it is also a truth that most of patients with eczema will be healed as they grow even if they are treated with TS.

Here I will address some information for the parents who decided not to use TS for their children.

First of all, you had better look for any doctor who will accept your intension that you wouldn’t like to use TS to your children. It might be difficult. But what I’d like to emphasize is that nourishing an atopic child without TS is sometimes misunderstood and regarded as medical abandonment or abuse to the child. You had better visit any doctor only for the counterargument against somebody’s blame to you in advance. I dare say the ability of the doctor is not important for that purpose. The fact that you visited any doctor periodically is important.

You must become an instant doctor also. Especially, you should know the signs of dehydration and sepsis.
http://www.babycenter.com/0_dehydration_11527.bc
http://kidshealth.org/parent/pregnancy_center/newborn_health_conditions/sepsis.html

There is no evidence that infantile patients with atopic dermatitis without using TS tend to develop dehydration or sepsis more easily than patients using TS.
However, parents who chose the way without TS tend to become reluctant to visit any hospital because they think doctors will blame them for non-use of TS. So the initial treatment for the patients who developed dehydration or sepsis can be delayed.

Parents must be smart and persevering. If your baby developed dehydration or sepsis and the doctor in charge told you should use TS, obey his instruction temporarily.
The doctor might even make threats that he can’t guarantee your baby’s life if you don’t agree to use TS. He is wrong medically. Any dehydration or sepsis can be treated ordinarily without TS. Glucocorticoids are only required systemically in such a case that the baby fell into septic shock and catecholamine became ineffective for rising blood pressure. The reason why the doctor wishes to use TS is that it is just easier to manage the patient at least temporarily (viz while the doctor is in charge). It is such a thing. Non-use of TS itself is never life-threatening from the viewpoint of emergency medicine.

But never discuss the matter with the doctor in charge. Only obey his instruction and agree to use TS. you can stop it afterwards. The situation can become life-threatening if other treatments are delayed. It is not the time of discussion.

Only endure even if the doctor blamed you for the former non-use of TS. He is only very sensitive in front of an infantile patient with dehydration or sepsis.

After discharging from hospital, you can stop TS again. You might have a psychological trauma due to the blame from the doctor. Forget it.
     
Anyway, never hesitate to visit hospital once you find any sign of dehydration or sepsis. That is the most important. Using TS temporarily or not makes no sense. You should give priority to the treatment of dehydration or sepsis.  

I am writing this blog under a certain ground. I am a skilled doctor of emergency medicine also. I am an ACLS experienced provider, a PALS provider, an ALSO provider and a FCCS provider still at present and formerly was an ACLS instructor and a JATEC (=ATLS) instructor.
As I had such a background, I might have been able to see severe TSW patients. I had a self-confidence that I could save the patients whatever emergent situations they dropped to.
I saved the patients with dehydration or sepsis many times without using TS. I declare that there is no life-threatening situation that absolutely requires TS application.

Another point to which the parents of atopic infants should be careful is nutrition.

 
The above chart is a growth chart of an infantile patient. The red curve means his body weight.
His parents stopped TS at the time of the top of the curve. The patient developed rebound and his serum protein and body weight decreased because of much exudation. The parents tried a kind of folk therapy but failed to maintain his body weight. He developed diarrhea and admitted to a hospital. The doctor in charge was my friend and treated without using any steroids. She examined his food allergy and looked for materials which are eatable for him and his body weight began to increase again.

As a result, what this baby needed was the examination of food allergy and nourishment by the eatable meal.
The patient had been fed by breast. Food allergens transfer from mother to baby by breast feeding. If the patient had been fed by artificial allergy-free bottle, he wouldn't have needed so much TS and wouldn’t have developed rebound. The crime of steroids exists in that they cover eczema and make the cause search difficult too.

Psychological care for the children is also important.
Smile always in front of your baby. Never look at the skin too much but look at the eyes of your baby.
Always be bright and cheerful. If you feel sad, your child will feel guilty.
You might be afraid that the child would ask of you why he or she suffers from eczema. But the child will say one day  to you “I am sorry for my suffering from eczema.” At that time, you would first recognize how your attitudes distressed your child.

Never discuss emotionally with the other parent in front of the child about his or her eczema. Smile always and keep strength as a parent of your precious child.

・・Sorry, I was not a good father. It was so hard for me to say the above phrases even if they are absolutely right. I always felt myself hypocritical.

One day when I told the above routine phrases to the parents of a patient, I suddenly become very very sad and really dropped tears. They never stopped. I couldn’t continue the out-patient work on the day.
After a while, I submitted my resignation to the hospital. I couldn’t continue my work anymore. It was my threshold.

I think you, parents of atopic children have threshold too. OK, I am also not so strong in fact. Anyway, let's start from what we can do. So I am now writing this blog. You too smile to your baby.
  
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.
 

2013年6月18日火曜日

Is moisturizing really a help to cure?

Please refer to the following article also for avoiding misunderstanding.
http://mototsugufukaya.blogspot.jp/2014/11/eczema-of-infants-may-be-prevented-by.html


There is a kind of faith that moisturizing is absolutely good for the skin. Do you think it is right?

There is an article about the relation between the environmental humidity and the mice skin.

Abrupt Decreases in Environmental Humidity Induce Abnormalities in Permeability Barrier Homeostasis. J Sato et al. J Invest Dermatol. 2002 Oct;119(4):900-4

 In the study, mice were divided to two groups. One was kept under a humid environment (relative humidity (RH) >80%) and the other under normal environment (40%<RH<70%) for the first two weeks. Then both were moved to a dry environment (RH<10%) for the subsequent one week. TEWL (trans-epidermal water loss: the indication of epidermal barrier vulnerability) was measured every day after moving to the dry environment.

The skin barrier function was better in the normal to dry group than in the humid to dry group. Especially for the early three days TEWL of the latter increased extraordinary.

The above graph shows DNA synthesis of epidermis which means keratinocyte proliferation in the early three days of both groups. The humid to dry group was delayed for one day in DNA synthesis compared with the normal to dry group.

Moisturizing increases the micro-environmental humidity very near to the skin surface. It means the protection by moisturizer works to delay the barrier function recovery.

There is another study. It is about premature baby and incubator humidity. Nurture in the humid environment (RH75) delayed the maturation of infantile skin compared with the normal environment (RH50).


Ambient humidity influences the rate of skin barrier maturation in extremely preterm infants. J Ågren et al, The Journal of Pediatrics,Volume 148, Issue 5 , Pages 613-617, May 2006

So excessive moisturizing do harm to skin recovery by delaying keratinocyte proliferation. I reccomend you should use no or less moisturizer if you want to advance recovery of the skin barrier.

If fact in Japan some of my friendly dermatologists adopt this strategy for patients with TSA. They recommend not use any moisturizer though they know the method is really a hard-landing.
They even advise not to drink too much water because exudation from the eczema itself makes the skin surface humid and it can be decreased by restricting drinking water. The method is not easily recommended because there is a risk of dehydration. But as far as from the viewpoint of accelerating recovery of the skin barrier, the method is right.

On the other hand, some patients with TSA prefer soaking in the bath for a long time. They spend several hours a day in the bath-tub. It is because they feel comfortable only in the hot water (=RH 100% environment). They even sleep in the bath-tub because they can’t sleep at all in the bed because of severe itching.
Such patients are not absolutely wrong. Their way might delay the skin barrier to recover. But they only selected less severer method which they can stand on the way to withdrawal.

So if utilizing any moisturizer is comfortable for your skin, it is not necesarily wrong to apply it. However, it is not a right idea if you think moisturizing is absolutely useful or necessary for the damaged skin. 

Note: It is exceptional about 100 thousand Da hyaluronic acid.
http://mototsugufukaya.blogspot.jp/2013/06/hyaluronic-acid-of-around-100-thousand.html

You will understand by using it. It never is a moisturizer but a  kind of nutrient for keratinocytes. Viscosity is lower than usual hyaluronic acid lotion. Efficacy as a moisturizer is low.

Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

2013年6月17日月曜日

The mechanism of TSA and TSR

Topical steroid addiction (TSA) is thought to be accociated with the atrophy of epidermis due to steroids. Cork in UK explained the mechanism by the balance of protease and its inhibitor working for collapse of corneodesmosome. Cork thought that topical steroids (TS) up-regulate the activity of the protease.
 
New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions. MJ Cork etc. J ALLERGY CLIN IMMUNOL Volume 118, Issue 1, Pages 3-21 (July 2006)

However, there was not a clear evidence that TS really up-regulate the protease (SCCE or KLK7). Moreover, the study about the effect of corticosteroids to keratinocyte revealed that TS don’t up-regulate the corresponding genes directly at least.

Kallikrein Expression and Cathelicidin Processing Are Independently Controlled in Keratinocytes by Calcium, Vitamin D3, and Retinoic Acid. Shin Morizane et al. Journal of Investigative Dermatology (2010) 130, 1297–1306

On the other hands, protease activities are reported to be increased in the lesion where TS were applied for a long time.

Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients
Komatsu N et al. Experimental Dermatology Volume 16 Issue 6 , (June 2007)

Komatsu in Japan confirmed that protease activities are increasing in the area TS were applied and the activities seem to be suppressed by inhibitors. The results match the theory of Cork.
   
How should we think of them? I think the protease activities are increased by TS not directly but indirectly.

There is a similar example. Filaggrin, which is an important component for skin barrier, is reported to be up-regulated by TS directly.

Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation. Stojadinovic O et al. J Biol Chem. 2007 Feb 9;282(6):4021-34

However, TS has another effect to filaggrin. TS shift immune balance from Th1 to Th2. Th2 cytokines act to decrease filaggrin production. So TS have two aspects. They directly up-regulate filaggrin gene while indirectly work to suppress its production. As a total, TS seem to act to decrease filaggrin.

Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest. 2013 February 1; 123(2): 917–927.

Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis. Demerjian et al. Experimental Dermatology, 18, 643–649,2009

So I support Cork’s theory at present. There is no contradiction though the theory still contains some hypothesis.
On the other hand, I feel Cork’s theory is not sufficient to explain the whole procedure of TSA. A sort of Th2 cytokine storm occurs just after withdrawal from TS. TSA should be explained by the action not only to epidermis but also immune system such as lymphocytes.

I think TSLP (thymic stromal lymphopoietin) produced by keratinocytes has another key in TSA mechanism.
It is because TS increases TSLP activities of keratinocytes and TSLP acts to shift Th1/2 balance to Th2.
 

 
Let's move to the subject of topical steroid resistence (TSR). There is an interesting article about TSR and glucocorticoid receptor (GR). TS work by attaching to GR in the cytosol. There are two kinds of GR, that is, GR alpha and GR beta. GR beta is a kind of dummy. If glucocorticoid attaches to GR beta, it never send signal to genes. So the ratio of GR alpha/beta is very important. If the ratio of GR alpha/beta of a lymphocyte decreases, the lymphocyte becomes insensitive to glucocorticoids.

Increased expression of glucocorticoid receptor β in lymphocytes of patients with severe atopic dermatitis unresponsive to topical corticosteroid. Hägg et al, British Journal of Dermatology, Vol. 162 p318–324, Feb. 2010

Hägg in Finland studied lymphocytes of patients with atopic dermatitis and revealed that the ratio of GR alpha/beta is decreasing in patients with resistance to TS.
The mechanism of TSR is known to be due to super-antigens produced by Staphs on the skin. However there seem to be more than two mechanisms in TSR according to Hägg’s theory.
  
Moreover, there appeared another interesting article. Inui in Japan reported a case with TSR in which he studied GR alpha/beta balance of the patient’s lymphocytes. He must have expected the same result as Hägg’s. But the lymphocytes expressed low GR alpha and very few GR beta.
The patient had used TS for a long time and it is considered that TS had once worked well. So the characteristic of GR expression should not be considered as congenital.

How should we think of them? I think GR beta expression can be a kind of protection of the cells against excessive glucocorticoids. At first the cells confront to excessive glucocorticoids by increasing GR beta while after a long time lymphocytes with enough amount of GR alpha can’t survive under continuous stimuli by glucocorticoids. As a result, lymphocyte with little GR expression only can survive.
It is only a hypothesis of mine. But I can’t explain Inui’s case by other ways.

When patients feel ineffectiveness to TS, several reasons should be considered. One is a simple reason that the applied TS were too weak to calm the eczema down. And the others are TSA and TSR.
TSA is associated with the epidermis atrophy and the effect to keratinocytes to produce TSLP.

TSR seems to be the effect to lymphocytes immigrating to the eczematous lesion. There seem to be two mechanisms, that is, one due to Staphs on the skin and one associated with GR alpha/beta balance.
 

For the usual patients, the above classification of mechanism might be hard to understand and even boring. But understanding the mechanism is really useful because the hints for treatment also exist in its inside.

In 2012, Matsuoka in Japan reported a very interesting article.

Periostin promotes chronic allergic inflammation in response to Th2 cytokines. Masuoka M et.al J Clin Invest. 2012 Jun 11.

In the article, she described the existence of a closed circle through periostin, a kind of protein produced by fibroblasts.
As the above vicious circle is closed, it must be hard to stop the reactions instantly once it began to rotate. Steroids work to stop almost all reactions consisting of the circle. But as the effect is so strong and the vicious cycle is also powerful, the rotation might develope a rebound after discontinuance of steroids.
Note that the circle contains the keratinocyte as one component. TSA is peculiar to topical application to the skin.

There is a kind of medication which suppresses only TSLP reaction of epidermis and doesn’t suppress lymphocytes at all. Such a medication may not be so strong to calm the eczema down but also not cause rebound after discontinuance.

Efficacy of Combined Peroxisome Proliferator-Activated Receptor-α  Ligand and Glucocorticoid Therapy in a Murine Model of Atopic Dermatitis. Y Hatano et al.  Journal of Investigative Dermatology (2011) 131, 1845–1852

Hatano in Japan reported PPAR alpha ligand is one of such medications. He revealed that a kind of PPAR alpha suppresses the rebound after TS application in experimental atopic mice.

As for PPAR alpha ligand ointment, I have tried to some Japanese patients since one year ago. I will be able to report the result soon.

Even if there are very few doctors who admit the existence of TSA/TSW around you, there really exist some researchers who are interested in the phenomenon. So there also exist a hope in the future. 
 
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

2013年6月16日日曜日

Phototherapy (narrow band UVB therapy etc)

Some of the patients who are reading my blog may have experience of phototherapy.
It is not a bad idea. Ultraviolet rays can suppress the eczema in certain patients. There is no report of rebound after phototherapy like TSA.
However, there are a few problems which tend to be overlooked. One of them is about the amount of light.

For example, there is a portable device for NB-UVB phototherapy like the below.

According to the manual, you use this apparatus like this (almost contacting directly to the skin).

How much is the amount of the light? You can measure it by yourself. No, you should measure it rather than you can.

You could find a measuring instrument on website and purchase it. It is not so expensive. For example, one in the below photo costs JPN 1,490 (= USD 15).

 
 Let’s try to measure it.

The value was 2.3W/m2.


 Theoretically, UVB therapy should be performed after the measurement of MED (minimal erythema dose) of each patient. It is because the reaction to ultraviolet rays differs by patient. Averagely it is 0.75J/cm2 in UVB. You are to start from one half or two third of the MED dose usually.

 An example of MED measurement

You need to convert W/m2 to J/cm2. The amount of light (J/cm2) is the product of the intensity (W/m2) and time (minute). I made a useful sheet as the below. When the intensity is 2.3W/m2, the time required to obtain 0.75J/cm2 is about 54min.

It must be difficult to treat the whole body by this small apparatus. I think the most reasonable usage of this apparatus is a challenge test to determine if phototherapy works to your eczema. You can treat a small area by irradiating every day for 10 minutes for example. The accumulated sum of the amount of light should be recorded as I write in the followings. 

In clinics or hospitals there are larger and stronger apparatus. However, remember that sometimes the dose (amount of light) is not enough because some doctors are afraid of accidental iatrogenic burning. Doctors have various policies. Some prefer scientific approach by measuring the intensity of the apparatus while others prefer riskless and empirical approach starting from very low dose and then increasing gradually. Under the latter doctors, patients might misunderstand that phototherapy is not useful.

So I believe patients had better purchase their own UVB checker and measure the intensity by themselves. The intensity depends on the distance from the apparatus. Also it depends on the age of light bulb. Even if the apparatus is large, the amount of light is not always enough because it depends on the distance, light bulb age and irradiation time.

The eczema may subside according to the accumulated dose. The dose for efficacy differs by patient. What is obvious is that you are not to be cured if the dose is too small. You should record the dose of every treatment, calculate the sum and compare it with the severity of eczema by yourself.

There are other methods than NB-UVB in phototherapy. They are the eximer laser and the UVA1. The result by eximer laser varies less than NB-UVB because the distance from the handpiece is fixed.

 Eximer laser treatment

There are several articles suggesting that phototherapy could help the recovery from TSA. For example, in the following article, Eximer laser is reported to be more useful for subsiding prurigo type of atopic dermatitis than topical steroids. As I have already written, prurigo type is often accompanied by TSA and hard to be treated by TS.
   
Excimer laser vs. clobetasol propionate 0•05% ointment in prurigo form of atopic dermatitis: a randomized controlled trial, a pilot. Brenninkmeijer EE,et al. Br J Dermatol. 2010 Oct;163(4):823-31.
   
On the other hand, there is another way to confirm if your eczema reacts to phototherapy. It is a travel to the area where natural UVB by sunlight is strong. For example, the intensity in Hawaii at noon in May is about 545 microW/cm2 (=5.45W/m2).
http://pets.groups.yahoo.com/group/UVB_Meter_Owners/message/3615

It is nonsense for patients living in Hawaii to use the above handy apparatus. They can be exposed to over the twice more intensity of UVB by only taking a walk outside.

I remember my journey to Sri-Lanka when I was young. As I was interested in UVB in the countries right on the equator I carried my UVB checker with me and measured. I couldn’t measure it because the intensity was over the upper limit of the apparatus.

There were patients with atopic dermatitis also in Sri-Lanka. It means phototherapy doesn’t always work for all patients.

I have some friendly doctors in Russia. One of them asked me once if I could send a certain sunscreen cosmetics made in Japan which was available in Russia at that time. She thought it must be more reasonable if I purchased it in Japan and sent it to her.

I have never seen the sunscreen in Japan but the manufacturer was a famous Japanese company. As I had a friend in that cosmetics company, I asked if there was any product of the similar ingredients.

He said, “Doc, this sunscreen is really a product of our company. It is made in Thailand and directly exported to Russia. So it is not available in Japan.”

“It’s OK. But if it is a product of your company, there must be a similar product. My friend will be satisfied with it.”

“Sorry to say, we don’t have a similar product in Japan.”

“Why?”

“In fact the product contains no ultraviolet-protective ingredient. There are very little ultraviolet rays in Russia. So our company doesn’t add any ultraviolet-protective agent to the sunscreen. What is written as a sunscreen is no more than imaging up. Maybe such an expression is not illegal in Russia differently from in Japan”

This is an episode of digression. But I think that Russian patients with eczema have a greater possibility of improvement by phototherapy than patients in Sri-Lanka.


This is a sign board of my clinic on the top of the building. As I am now a cosmetic surgeon, I must protect my clients from aging by ultraviolet rays. So I am selling sunscreens containing true ultraviolet-protective agents in my clinic and indicating UVA intensity on the sign board in real time for enlightening.
But I know ultraviolet rays have an aspect of good efficacy to the skin also.

There is no medication without side effects. TSA is a terrible side effect of TS but TS has a useful aspect also.  It is just like human beings. Any good person has some defects while any bad person has a few good aspects too. Nothing is absolutely bad or good.

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2013年6月14日金曜日

Words

I remember one patient. She was the last patient whose life I saved.
She had have been addicted to steroids and I had helped her withdrawal. She became better and didn’t appear to me for a while. Well, it is often the case with the patients. Most patients don’t come to me after becoming well.

One day she appeared accompanied by her parent. She was very skinny and suffering from anorexia. She had suffered from a kind of leukemia also. She couldn’t come to me because she was found to be suffering from leukemia and admitted to a hospital. Systemic steroids were administered as a treatment.
After the remission of leukemia and steroids were discontinued, she developed eczema again. It seemed to be just like the rebound. So she came to me again.

She was admitted to our hospital for the purpose of intravenous nutrition. While I was inserting a catheter to her subclavicular vein, I thought it might be my last whole body treatment to a patient. I had just sumbitted my resignation the day before. I had been so tired and depressed by treating thousands of TSA patients.

And she told me as the followings.
"It doesn’t matter whether steroids are good or bad. If my leukemia recurs, should I use the steroids again?
Have you ever seen such a patient like me? Is there any patient whose skin is so dirty like me?
Doc, please don't leave me alone. Don’t go away from me. There is no place to stay for me."

I answered.
"It’s all right.
You become cured if you continue to live. You are to be healed if you only continue to live.
It’s all right.
You can’t be cured if you died.
So please eat a meal as much as you can. You can’t become healed if you died though your disease can be cured."

"Doc, is it really OK? Will my skin become clear? Is there anybody who has so dirty skin like me?"

"It’s OK.
You are to be cured if you only continue to live.
How many years have I seen you? You have been cute and beautiful since your first visit. As you are originally cute, you become clear."

I repeated above sayings but thought that it was a hard work for me because I myself had lost the purpose of my living at that time. I only repeated the phrases vacuously seeing the far landscape from the window.
That was my work.

The day after, she developed DIC shock due to sepsis. Her sayings must have been from a kind of mental confusion just before it. As I had felt an abnormal atmosphere, I had checked fibrin-d-dimer in serum and had administered FOY for prevention of DIC. I saved her life. I dare to say I was a skilled physician though my specialty was dermatology. I saved patients’ lives many times like this.

After my retirement, I telephoned to her because I was anxious about her. She answered the phone and said she was doing well. I felt relieved.

Words from a doctor might be the best medication for patients.
However, I think it is necessary for the doctor to be skilled enough. If the doctor had good skills, his words would become a medication.

I have not seen patients for a long time. I believe my skills are still alive and I hope my words on internet work for you.

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Disinfectant therapy to staphs on atopic skin and the topical steroid resistance (TSR)

I don’t know if the same kind of therapy exists in other countries than Japan. I have never found the similar therapy in other countries by the Pubmed (medical scientific article sauce, http://www.ncbi.nlm.nih.gov/pubmed).

The disinfectant therapy includes various methods.Theoretically there are as many methods as the number of disinfectants. Anyway, the disinfectant therapy means applying a certain disinfectant to the patient’s skin, waiting for a while (usually a few minutes) and washing the disinfectant away by shower. That is all.

Povidon-iodine and electrolyzed strong acid aqueous solution are both preferable disinfectants. Do you know the electrolyzed strong acid aqueous solution? It became popular in 90’s in Japan in the medical field. It is because the problem of MRSA (Methicillin-resistant Staphylococcus aureus) emerged at that time. The staphs could be sterilized by oral antibiotics more effectively than disinfectant but it would also increase the risk of emersion of MRSA. So various trials were done at that time in Japan and use of the electrolyzed strong acid aqueous solution in the medical field was one of them.

By search of Pubmed, I couldn’t find any article about the electrolyzed strong acid aqueous solution by non-Japanese researcher. So I am not sure if it is also used in the medical field in other countries. The solution is produced from the tap water, a bit of salt (NaCl) and a kind of electric device (Figure below).
The electrolyzed water around anode indicates low value in pH. The acid water below 2.7 in pH is the electrolyzed strong acid aqueous solution. It sterilizes every kind of bacteria nonspecifically.  The shortage is that the solution is unstable. So it is recommendable to purchase the device itself.  The device costs about JPN 50-100 thousand (USD about 500-1,000). The price differs by provider or the time to purchase. In fact, I have my own device in my clinic too. I sanitize environments around my operation room by that solution.


For atopic dermatitis, the below illustration will help you to comprehend the procedure. The illustration is from a brochure of a provider of the electrolyzed strong acid aqueous solution.

The solution doesn’t irritate the skin at all although its pH is very low. It is because the solution becomes just oxidized by the contact to the skin. It reduces the very superficial layer of the skin and bacteria to disinfect. The action is so instantaneous that it never damages the substantial skin. It is recommendable even for infants and children. And you don’t need to wash the solution away in several minutes like other disinfectants.

Povidone-iodine 10% solution is another disinfectant commonly used for the treatment of atopic dermatitis. It was first put forward in 1990 by Sugimoto, a pediatrician in Japan. He has written several medical articles about the method.

New successful treatment with disinfectant for atopic dermatitis. Dermatology 1997; 195(suppl 2):62–68.

The Importance of Bacterial Superantigens Produced by Staphylococcus aureus in the Treatment of Atopic Dermatitis Using Povidone-Iodine. Dermatology 2006;212(suppl 1):26–34

The photos below is the procedure.


First the patient applies povidone-iodine 10% solution directly to the skin. Note that there are many povidone-iodine liquid products. Some of them contains alcohol (for gargle) or detergents (for hand wash) and are not suitable for this therapy. Only 10 % simple aqueous solution can be used.

After 2-3 minutes the patient washes the disinfectant away completely by shower. The patient then applies emollients like simple white petrolatum. That is all.

Comparing the above two disinfectants, the strength as a disinfectant is maybe larger in povidone-iodine. But the stimulus is also more in povidone-iodine. Moreover, the povidone-iodine has the risk of sensitization while the electrolyzed strong acid aqueous solution does not. So I recommend the electrolyzed strong acid aqueous solution for patients who are not under skillful dermatologists.

The biggest problem of staphs on atopic skin is that it can cause the topical steroid resistance (TSR). Staphs produce a kind of toxins and they effect as superantigens which accelerate immune reaction nonspecifically. The patient who suffers from TSR develops ineffectiveness to topical steroids. The patient present very similar skin symptom to TSA and sometimes TSR is accompanied with TSA.

Here is a case with TSR and TSA. His eczema relapsed at the age of 18 after long remission period from infancy. The amount of TS prescribed in the former dermatologist for 5 years before the first visit to me is as follows.

age
Amount of TS (gram per year)
23
1595
24
1665
25
2178
26
1650
27
890

The patient reacted to TS at first but became to feel ineffectiveness since 27 years old. So the patient discontinued. The patient was introduced by the former dermatologist to me because of difficulties in treatment. The appearance of the patient at first visit was as the below photo.


How do you think his skin manifestation? It is so-called erythroderma but the point is that his skin manifestation consisted of very few elements. That is, the element was almost erythema only. In such a case, the TSA is not so severe. If he had various elements, especially prurigo, I judge his TSA is severer.

There are two possibilities of his ineffectiveness to TS; TSA and TSR.
You may say there is a possibility of contact dermatitis to TS or emollient etc. But the patient came to me after four months’ discontinuance of TS and he had never applied anything to the skin for that period. If he suffered from contact dermatitis to something, He must have recovered at that time. So contact dermatitis is excluded.

I examined the staphs on the skin by culture. There were enormous number of staphs. So I recommended the disinfectant therapy using povidone-iodine. Staphs cause TSR and worsen the dermatitis itself. Such patients may develop steroid-resistant dermatitis.

The above photo is one month after the first visit.

 
The above is three months after the first visit.


 The above is 6 months after the first visit.


 8 months
 10 months
1 year

1 year and three months after the first visit. He had never used any medication except for disinfectant and white petrolatum. So it is his original skin. The eruption seen at the first visit was TSR accompanied with TSA and was not of his original eczema.
The below is a flow chart summary for the better understanding.
Be smart and wise enough not to fail to recognize your own situations. Because only you can know the whole procedure of eczema and judge correctly.


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2013年6月12日水曜日

How long does the rebound period continue? Am I really suffering from TSA now?

Sometimes I am asked how long the rebound period usually continues. I am reluctant to answer to it because it differs by patient. Nevertheless patients expect any answer from me and ask again and again. So I used to answer that it is about 20 percent of the period in which you applied topical steroids.

It is my honest impression on average. But average is only average and doesn't always go for the individual patient. So I should rather refrain from answering.

When I explain TSA/TSW, I tend to refer to the cases easy to be understood. So the “typical” cases are presented. Such cases develop severe rebound for several months and then improve almost completely afterwards. But it is not a “typical” case in fact but an “understandable” case.

So I present here another case. She had used topical steroids since infancy until 23 years old. I could obtain her medical record by the help of her former dermatologist in charge.

 
The photos after the first visit to me are as follows. She had never used any steroids afterwards.



The photo of 96.10.8 is the absolutely addicted skin manifestation. Most dermatologists will diagnose it as atopic dermatitis with prurigo and comment “Prurigo type is usually hard to be treated”. I dare to say it is not correct. Atopic dermatitis with prurigo is often topical steroid addiction. That is why such a type is hard to be treated. In such cases topical steroids don’t work anymore.

Photos from 96.10.24 to 97.1.14 are series of the typical rebound aggravation. The rebound became the maximum in 97.1.14. It is Rapaport’s “Red burning skin syndrome”. From 97.3.25 her eruption began to subside. Though there were ups and downs, her skin manifestation began to change from the addicted one to the orthodox atopic dermatitis.

You can see an obvious demarcation around the wrists on the photo of 97.1.14. It is one character of rebound phenomenon.

There is a Youtube movie in which a patient talks about this demarcation. Please find it on the following website. http://www.youtube.com/watch?v=EX5qs9Viblg

Do you remember ITSAN’s symbol logo? I admire the illustrator. It is very suitable as a logo of TSA association.
 
You will not identify the demarcation on the photo of 99.8.10. Instead you can see eczema on flexor sides of elbows. It is an orthodox appearance of atopic dermatitis. There is few or less prurigo than in the photo of the initial visit. She had almost cleared the rebound.

But still she had eczema. She withdrew from TSA and came back to her original atopic dermatitis. Can you judge from what point in time her eruption has changed?

After withdrawal from steroids, the skin becomes very sensitive to every stimulus for a while. The patient’s skin can’t tolerate to even simple white petrolatum. The skin reacts to various stimuli at that period and the eruption is completely similar to original atopic eczema. Yes, it is the eruption of atopic dermatitis. But from the viewpoint of making much account of TSA, in a wider meaning, the patient could be regarded as staying still on the way of withdrawal.

From a certain point of time the patient's eczema becomes completely of the original one with no relation to former steroids application. But the point can't be correctly judged.

However, remember that original atopic dermatitis itself has a tendency to be healed naturally. Hypersensitivity after withdrawal also decreases as time passes. It is not important to judge the point of time dividing the two. Anyway the patient is on the way to improve.

Patients become very tired and depressed as time passes. My “understandable” case presentation is surely a hope for them at first but becomes a stress after much time has passed. And they ask the titled questions of me. “How long does the rebound period continue? Am I really suffering from TSA now? “

During early times of withdrawal it is surely hard to tolerate but what you should do is only tolerating it. But after enough time has passed and your eczema has changed to usual atopic dermatitis, you should do other efforts. Detecting and avoiding any stimuli to your skin. It is easy to say but difficult to carry out. But it surely is the wisest policy.

At that time you can even resume topical steroids which you must have thought you would never use again in your life. You might feel a humiliation but they would really work. For the better quality of life you can utilize them. What you are requested is only the care not to be addicted again.

Some patients prefer small tablets of oral steroids. Even though they are not informed of TSA/TSW, they fear topical steroids instinctively and empirically. But it is not a good choice because such patients are prone to be addicted to oral steroids psychologically. Needless to say, oral steroids are more harmful for your general health than topical steroids when they are taken for a long time. .

The female patient of my above presentation never used any steroids while I was her doctor in charge. I never told not to use them. I always only inform the possible ways. She herself decided. 
 
After my retirement I don’t know what way she would choose. I don’t care what way she went on but I really hope she is doing well now from the bottom of my heart because she was once a patient of mine.
 
 
Before withdrawal (during application of TS) all blood markers are suppressed and don’t reflect the real significance of eczema. They indicate only the amount of TS to make a sarcastic remark.

After withdrawal from TS, these markers increase rapidly and then decrease gradually reflecting the real skin conditions. If the patient is exposed to some aggravating stimulus, the values increase temporary.

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