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.