2013年7月27日土曜日

Ophthalmological complications

“You don’t need to visit any dermatologist including me, but you should visit an ophthalmologist periodically.” That was my habitual saying to patients with atopic dermatitis.

 There are several ophthalmological complications in atopic dermatitis. Well, I will make a question about it.

 You should clear the exam before treating your atopic dermatitis by yourself. Never feel easy about ophthalmological complications only because you are seeing some dermatologist. They see only your skin and never see your eyes.

 Which is the ophthalmological complication in atopic dermatitis?

a.cataract  b.retinal detachment  c.conjunctivitis d.keratoconus e.glaucoma

1.a  2.a,b  3.a,b,c,d  4.all 5.none

  Atopic cataract occurs suddenly. Though steroids can induce cataract, atopic cataract occurs regardless of steroid therapy. There were patients with atopic cataract several decades ago when steroids were not yet invented.

 Cataract has a tendency to develop a while after severe dermatitis has subsided. Some dermatologists criticize TSW insisting that TSW is the cause of cataract. But it is a ridiculous theory because the cause of TSW (A) is topical steroids. Bad dermatologists neglect their duty to give information about ophthalmological complication before the patients develop cataract and blame their TSW after the development of cataract. 

 When cataract is developed, the patient’s pupil becomes cloudy. It occurs one day and progresses in a few days. It is just like you have a drip of milk in your eye. Fortunately, cataract can be treated by operation. You can recover eyesight. Ophthalmologists might use eye drops of topical steroids for the purpose of conditioning the situations around the operation. You should not be so nervous but you can request of the ophthalmologist to refrain from using it if you never like to use it. Usually ophthalmologists are not so stubborn about topical steroids and accept your request.

 Anyway, your cataract should be operated not only because you could recover eyesight but also because it will help an early identification of retinal detachment.

 Retinal detachment in atopic dermatitis starts in the peripheral parts of the retina. It is the part of difficulty in examination. If there were untreated cataract, ophthalmologists couldn’t check the part.

 If the retinal detachment is identified early when it is small, laser therapy can stop the progression. So it is very important to find out as early as possible.

 Retinal detachment is considered to be caused by the repeated or frequent banging to the skin around the eyes. Mechanical vibration is an inducement. So we dermatologists often warn patients not to bang around the eyes but the stress of the patients become increased by the warning itself and they bang or spank more and more. Nobody seems to be able to stop it. So I recommend patients to visit an ophthalmologist at least. The damage would become the least by examining the retina periodically.

 Conjunctivitis is a symptom of allergy. Sometimes the cornea is also damaged mechanically because of the mucosal roughness of the eyelid side of the conjunctiva. Keratoconus is completely a complication of atopic dermatitis itself. The eyesight of the patient with keratoconus can be corrected by the contact lens.

 Glaucoma is the side effect of steroids or antihistamines if the ocular tension decreases by stopping those drugs. Glaucoma is never a complication of atopic dermatitis. So the answer of the above question is 3.

 I used to introduce all patients with atopic dermatitis to the ophthalmological department first of all before I myself see the patients. I am now retired but if I had continued to see TSA/W patients after resigning the national hospital, I would have studied ophthalmology and equipped with the instruments of funduscopy and slit lamps in my clinic. It is so important a problem.

 If the patient is an infant or a child, you need not become so nervous. But even a child also can develop cataract if the dermatitis is severe. Keep being careful.

 Now I will refrain my usual almost habitual saying again. You, patients with atopic dermatitis don’t need to come to dermatologists including me but you should visit to an ophthalmologist periodically. They will not prescribe any medicine but examine your eyes. It is very important.
 


PS: In Japan, patients can see an ophthalmologist (eye doctor) for the purpose of only examinations under the public health insurance at the cost of about 30 USD. Patients usually don’t need to make any reservation or appointment. I don’t know how much it costs or how hard it is to make a reservation overseas. If you have any experience of seeing an ophthalmologist, please leave a comment for the exchange of information.

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2013年7月16日火曜日

A report about a biological product for patients with atopic dermatitis.

 Have you heard of the medicine called a biological product? It is a practical application of the monoclonal antibody.
 There are various biological products available nowadays. Among them Xolair (Omalizumab) is the most promising for atopic dermatitis at present.


 Xolair was studied as a medicine for asthma. Patients with asthma often suffer from atopic dermatitis also. Some patients with asthma to whom Xolair was administered also improved their eczema. So doctors started to study the efficacy of the medicine for atopic dermatitis. Some reported Xolair was useful while the others reported not effective. There was no double blinded case-control study. The below report is the first double blinded case-control study about Xolair for atopic dermatitis though the population is small.

Immunologic Effects of Omalizumab in Children with Severe Refractory Atopic Dermatitis: A Randomized, Placebo-Controlled Clinical Trial. Iyengar SR,et al. Int Arch Allergy Immunol. 2013 Jun 27;162(1):89-93  

 The number of patients was 8 at the age of 4-22. They were divided to two groups of placebo and Omalizumab administration.
 They were all refractory patients (“All patients had severe AD that had failed standard therapy.”). Whole the treatment was discontinued one week before the first administration of the placebo or Omalizumab. The agent was administered by subcutaneous injection and the dosage of Omalizumab was 150-375mg every time. The frequency was every 2-4 weeks and the duration of treatment was 22 weeks.

 Total IgE, Free IgE, TARC and SCORAD values are picked up from the results of the article as the following table. How do you read the numerals?


 Omalizumab is an antibody to IgE. It binds to the patient’s IgE and inactivates it. The free IgE decreaseed and Th2 system also became inactivated.
 However, about the SCORAD which indicate the clinical severity of atopic dermatitis, the values decreased in both the placebo and Omalizumab groups. How should we understand the result?

 I consider there is a possibility that the placebo patients improved  by topical steroid withdrawal(TSW) for 22 weeks.

 In the article, the authors didn’t mention the result of the statistical analysis. So I did the matched Student’s t test to their results. The P value were as the following.
 

  At the 0.05% of the significance level, the placebo group improved while Omalizumab group didn’t improve.

 The author’s comment is as the following.
“The high rate of response to placebo has been well documented in these types of studies and, had any of the above published studies examining the clinical effects of anti-IgE included a placebo arm, a similar rate of response may have been seen.”

 Wait for a while. The phrase is likely to be skipped just carelessly but you ( the author) mentioned the patients were all refractory to the usual standard therapy, weren’t they? You admit such patients improved by the placebo treatment for 22 weeks and it is often the case with that kind of studies?

 Yes, atopic dermatitis has a tendency of natural healing. But the enrolled patients were “All patients had severe AD that had failed standard therapy.” I suppose you should not have forecasted their natural improvement before the study.

 The price of Xolair is about USD 350 per 75mg. It costs about USD 4200-21000 for 22 week treatment.
 Here I should clarify my stance about this therapy. I dare say I will buy Xolair and administer to my child if he or she suffers from the refractory atopic dermatitis. If I were a sufferer, I definitely buy the treatment. The problem about the above article is only the SCORAD result of the placebo group. The results of blood examination are clear and convincing. The significance of SCORAD is over 0.05 but I believe it will decrease if the population becomes larger.
 The cost is really high. But fortunately I can afford it. I will pay for the medicine even though there is a small risk of anaphylaxis or carcinogenicity due to immunosuppression. I take the merit heedless to the risk of this medicine.

 But I know well all the patients can’t try the treatment because of the financial problem. Don’t worry. You could also become improved only by discontinuance of the whole treatment for 22 weeks just like the patients of placebo group.

 Yes, it is the essence of the TSW. Patients feel strong anxiety to the situation of “nothing to do”. Placebo patients in the above article might have worsened temporarily but they could stand it because they thought they were through a treatment. Doctors could also stand the stressful situations because they thought they were scientifically right. Do consider. If the placebo patients remain worsened, the best scientific outcome could be obtained. Otherwise the doctors couldn’t stand seeing worsening patients without any treatment and must have recommended to resume topical corticosteroids.

 However,what a happy ending of the study! All patients became improved in the above article and the efficacy of TSW was also confirmed. A toast to the authors!


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2013年7月11日木曜日

The bankrupt of the regulation of cortisol level in the skin tissue might be the essence of TSA.

Recently it has been revealed that epidermal cells produce cortisol (corticosteroid) by themselves. Topical steroid addiction (TSA) is considered to be related with the skin atrophy which causes the barrier dysfunction. The bankrupt of the regulation of cortisol concentration in the skin tissue might be its ground.

 The concentration of cortisol in the skin tissue is kept lower than in the blood.
 According to the following article about thermal injured patients, for example, plasma total cortisol took the value of 8.8μg/dl, free (protein unbound) cortisol 1.7μg/dl and tissue (skin) cortisol 0.74μg/dl.

 Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation.Cohen J et al, Crit Care. 2009;13(6):R189. Epub 2009 Nov 27.
   
 In healthy subjects as a control, the tissue cortisol was 0.20μg/dl. Only a fraction of the concentration in the blood is detected in the normal skin tissue outside the blood vessels and the value increases once inflammation such as burn occurs.

  By the way, epidermal cells, hair follicular cells and fibroblasts in the dermis can produce cortisol by themselves. What is more interesting is that the production of cortisol by those cells is amplified by the skin tissue cortisol. There is a positive feedback mechanism.


On the other hand, there is  also an enzyme that inactivates cortisol in the sweat gland. The concentration of cortisol in the skin tissue is controlled by those factors. The following figure is what is summarized.

11βHSD1 is an enzyme that converts cortisone (inactive steroid) to cortisol (active steroid) while 11βHSD2 is an enzyme that converts the latter to the former.
 What is the meaning of the positive feedback mechanism of cortisol production? It must be for the purpose of increasing the skin tissue concentration of cortisol rapidly in case of any inflammation such as burn occurs.

 If topical steroids are applied to the skin, epidermal cells or fibroblasts react to TS and produce cortisol. The increased cortisol effects to the cells themselves and suppress their own proliferation. In case of systemic steroids such as oral steroids, the effect to the skin tissue concentration is not so much because blood vessels regulate cortisol not to transfer too much to the skin tissue.

  Now you can understand how abnormal the situation of continuous use of topical steroids to the skin is. Physiologically the concentration of cortisol in the skin tissue is kept considerably low. Topical steroids violate the controlled situation.

 After stopping topical steroids, the epidermis becomes thicker than before TS application temporarily. It means the skin tissue lacks enough steroids temporarily.

 
1A:Before application of TS, 1B: thin epidermis after TS application, 1C 1D 1E: temporarily thickened epidermis after discontinuance of TS
(Morphologic Investigations on the Rebound Phenomenon After Corticosteroid Induced Atrophy in Human Skin. Zheng P, et al. J Invest Dermatol 82: 345-352, 1984)
 
 The fact that epidermis becomes thick means that the steroid deficiency has occurred. But what is the mechanism of the deficiency? There must have been too much steroids.
 
  One of the possible mechanism is as the following.

  11βHSD1/2 balance, which is 11βHSD1 dominant in the epidermal cells normally, changes to become11βHSD2 dominant after considerable dose of TS application.

 After discontinuance of TS, the skin tissue cortisol becomes low temporarily. Inactive form of steroid (cortisone ) is accumulated within the cell. After 11βHSD1 reactivation, skin tissue cortisol will be produced but from the accumulated cortisone. It never is a normal condition. The gene coding cortisol will not be up-regulated under such a condition and various proteins which are related to the gene will not  also be produced. So the skin remains fragile and the barrier dysfunction continues.

 It is only a hypothesis. However the temporarily deficiency of steroids after discontinuance must be explained in any way.  
 
 The below figure shows 11βHSD1/2 expression of the normal skin (brown means 11βHSD) . 11βHSD1 is expressed on the whole cells of epidermis while 11βHSD2 is expressed only on the outer layer. Obviously there is a regulated balance of 11βHSD1/2 in the normal conditions.
 (Keratinocytes synthesize and activate cortisol.Cirillo et al.J Cell Biochem. 2011 Jun;112(6):1499-505)

 The concentration of cortisol in the skin tissue is kept low basically and the constituent cells produce or inactivate cortisol according to the inflammatory status. Topical steroids application violates its harmony and constituent cells become instable after TS application. I consider it might be the essence of TSA existing as the ground of the barrier dysfunction caused by TS.
 
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2013年7月1日月曜日

Do topical steroids prolong atopic dermatitis?

Apart from the problem of TSA/TSW, there exists another important problem which most of the patients are anxious about.
 
“If the population of patients with TSA is 10 or 20% as Dr. Fukaya mentions, why is the number of patients with atopic dermatitis increasing? Is there any possibility that TCS application prolongs AD and postpones the natural healing?”
 
 In fact, the number of patients with AD has been increasing after TCS was produced and came onto the market more than half a century ago . There is no other disease that a population of the patients increased after a medicine for the disease had been produced.
 
 One Japanese researcher presented an interesting article in 2010 about experiments using AD model mice. Mice treated with a kind of chemicals on the skin repeatedly develop AD like dermatitis. He compared the skin (ear) thickness and scratching behavior of TS treated group and non-treated group. The result revealed TS improve the skin thickness but argument the frequency of scratching behavior.The results were the same when he changed mice strain, chemicals or the kinds of TS.
 
Repeated topical application of glucocorticoids augments irritant chemical-triggered scratching in mice. Fujii Y et.al. Arch Dermatol Res. 2010 Nov;302(9):645-52.

 
The above figure is from Fujii’s article. TPA is a kind of chemical which causes eczema. The white bar is of mice not treated with TS and the black bar is of TS-treated. TS suppress the eczema (ear swelling) but increase scratching frequency.
 
Then, he measured the concentrations of the substanceP and NGF(nerve growth factor) of the skin lesion which are both associated with itch sensation of the skin.  Both were increased in the TS-treated lesion than non-treated lesion.
 
To explain instinctively for easy understanding, repeated stimulation by antigens causing eczema which subside apparently by application of TS, also cause decreased threshold of scratching. Inflammation that TS suppress is substantially a protection against extrinsic stimuli. After the suppression by TS, another mechanism of protection must start if the stimulus doesn't disappear. It is the mechanical protection by scratching behavior.
 
Some patients would agree in the result of experiments from their own experience. The itching just before the withdrawal when those patients felt ineffectiveness to TS seems to be very offensive and strange. The itching stays very inward and they often tell the itching after TSW is also itching but very different from that of before withdrawal. The latter is far better than the former.
 
The above mentioned Japanese researcher is Fujii in his name and he belongs to Astellas pharma Inc. which is the manufacturer and provider of Protopic ointment.
 
As I have already written, the history of Protopic (or Elidel in Europe) is dramatic. In around 2000, Protopic appeared like a savior of the TSA problem. We dermatologists all thought that TSA or rosacea-like dermatitis due to TS at least in the face would disappear in several years. But several cases were reported that Protopic also caused rosacea. All people concerned were shocked and thought “ What is the merit of Protopic if it also causes rosacea?” I imagine Fujii was also one of them. By the way,there was another preceding report by other researchers that Protopic was superior to TS in the suppression of scratching behavior.
 
 Inhibition of scratching behavior associated with allergic dermatitis in mice by tacrolimus, but not by dexamethasone. Inagaki N et al. Eur J Pharmacol. 2006 Sep 28;546(1-3):189-96.
 
 Fujii might have been interested in it and retest it. The results were more than he expected. He has revealed not only the superiority of Protopic to TS but also the negative aspect of TS about the prolongation of the disease. Fujii concluded the end of the article like the following.
 
In summary, this study is the first to show the potential of topical glucocorticoids to augment itch sensation, not via the augmentation of inflammation. This phenomenon might result   from   the augmentation of   SP   and   NGF   production, along   with   nerve  fiber   extension,   at   the   application   site.
Given the profound impact of scratching on skin inflammation, these findings might explain the etiology of the exacerbation   of   atopic   dermatitis   and   other   dermatitises, which occurs after long-term or inappropriate use of topical glucocorticoids.
 
 What should Fujii or Astellas pharma inc. do next?  Can they promote Protopic successfully by introducing the above result of experiments to dermatologists who are prescribing TS everyday?
 TS are the main tool for most dermatologists and they can’t replace all to Protopic. Maybe dermatologists feel stressful and even emotional if Protopic were promoted in such a way.
 
From the viewpoint of patients, I am certain that Protopic should be promoted like that. Though I or my children are not eczema sufferers, I would prefer Protopic to TS if I must use definitely either of the two. Protopic has a risk of carcinogenesis. But I would take the risk of it rather than a risk of prolongation of healing by TS because the former seems to be much rarer than the latter instinctively (I only mean there is not such a statistics).
 
About the relation with my hyaluronic acid lotion, it certainly prevents the atrophy of the epidermis due to TS and development of TSA. I definitely recommend using it to TS users. But argumentation of scratching behavior due to TS would not be suppressed by it. So I recommend not to use TS for so long a time even if the patient applied my hyaluronic lotion. That is my thinking at present.
 
 PS; I uploaded my self-introduction video on Youtube because some of you might have intetest in what a guy I am. Please watch to enjoy it.http://www.youtube.com/watch?v=oh8uz7OObr8&feature=youtu.be
 
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