Chapter 14 “Poor Response”- Steroid Resistance
Steroid resistance is a concept different from steroid addiction. According to Dr. Cork, steroid addiction is the condition where topical corticosteroids, which effectively suppress eczema initially, destroy the epidermal barrier over long-term usage, leading to rash aggravation caused by a slight irritation and inducing the rebound phenomenon when the application is discontinued.
On the other hand, steroid resistance means a poor (or poorer) reaction to topical steroids. Telling steroid addiction from steroid resistance is difficult because patient complaints are steroids are not working any more in both cases. What can be said is that steroid-resistanted atopic dermatitis patients will not experience rebound if they are not addictive to steroids.
At present, it has been revealed that steroid resistance is associated with superantigens produced by staphylococcus aureus on the skin surface.
Superantigens, steroid insensitivity and innate immunity in atopic eczema.
By D Leung published in the Acta Derm Venereol 2005; Suppl. 215: 11–15
Superantigens interact with T cell receptors to activate T cells, and also interact with steroid receptors.
Steroid resistance is a concept different from steroid addiction. According to Dr. Cork, steroid addiction is the condition where topical corticosteroids, which effectively suppress eczema initially, destroy the epidermal barrier over long-term usage, leading to rash aggravation caused by a slight irritation and inducing the rebound phenomenon when the application is discontinued.
On the other hand, steroid resistance means a poor (or poorer) reaction to topical steroids. Telling steroid addiction from steroid resistance is difficult because patient complaints are steroids are not working any more in both cases. What can be said is that steroid-resistanted atopic dermatitis patients will not experience rebound if they are not addictive to steroids.
At present, it has been revealed that steroid resistance is associated with superantigens produced by staphylococcus aureus on the skin surface.
Superantigens, steroid insensitivity and innate immunity in atopic eczema.
By D Leung published in the Acta Derm Venereol 2005; Suppl. 215: 11–15
Superantigens interact with T cell receptors to activate T cells, and also interact with steroid receptors.
The above figure shows the mechanism of steroid resistance that may occur in various inflammatory disorders including atopic dermatitis (AD). In AD patients, staphylococcus aureus: 1) increase the number of GRβ(glucocorticoid receptor beta, which is antagonistic to effective GR and negates the effect of steroids; and 2)act on kinase called ERK (gray circle in the center of right half) to phosphorylate GR outside the nucleus so that GR can’t enter the nucleus.
In the above figure, SEB, TSST-1 and SEE are all superantigens produced by Staphylococcus aureus and induce proliferation and hyperplasia of lymphocytes (this is why they are called superantigens). PHA also induces proliferation and hyperplasia of lymphocytes, which is suppressed by dexamethasone (corticosteroid). But superantigens cannot be suppressed by steroids. That is, inflammation won’t subside with steroids and this is a phenomenon called steroid resistance in AD. The more staphylococcus aureus colonizes, the less effective steroids become. This is the reason why steroid resistance is different from steroid addiction.
It has been long known empirically that topical steroids are more effective when mixed with antibiotics than when administered by itself (see the above table). Antibiotics suppress the activity of staphylococcus aureus and thus overcome steroid resistance. Dr. Leung revealed the relationship between steroid resistance and superantigens produced by S. aureus.
By the way, Dr. Takehara (Kanazawa University) says in his book that it is the wrong idea that response to steroids gets gradually poorer or steroids are ineffective for some patients (see Chapter 3 of Machigai-darake-no-atopi-chiryo, Many Misunderstandings for Atopic Dermatitis Treatment). I think this statement is wrong. It is true that it has been unknown till recently that superantigens generated by S. aureus are involved in steroid resistance. But this phenomenon has been clinically observed for decades. As mentioned in the previous chapter, there are many poor-response cases that are difficult to explain with steroid allergic contact dermatitis. To answer the patients’ inquiry for a poor response in this educational book, he should have referred to the possibility of steroid addiction due to too much use of corticosteroids, or an increased colony of S. aureus and been advised to consult the doctor. Neglecting steroid resistance caused by S. aureus and escalating the steroid potency in response to rash aggravation will just escalate steroid addiction.
As to measures against S. aureus, dermatologists supporting steroid withdrawal have different opinions about which measures to take:
1) Antibiotics;
2) Antiseptics; or
3) No measures.
I used to choose the second option and topically apply antiseptics (applying povidone-iodine to rinse away after 10 minutes, which is the method suggested by Dr. Sugimoto, Chiba University). I can accept option 3) but object choice 1) (application of antibiotics). Thorough sterilization is difficult, which is indicated in the reference material. In the first place, S. aureus adheres more readily to the AD patient’s skin because such patients cannot produce enough physiological antimicrobial substances such as HBD (human beta defensin) and antibiotics may induce resistant bacteria such as MRSA. MRSA leads to concurrent blood poisoning or limits the selection of antibiotics available as necessary and in some cases surgery is required for some reasons (e.g., retinal separation). There are physicians who prescribe antibiotics without hesitation at their clinics. Antibiotics might be effective in order to prevent patients from dropping out of the withdrawal regimen, but should be administered prudently.
Antiseptics cannot eliminate bacteria thoroughly either, and have the risk of developing contact dermatitis or destroying the skin barrier with a small amount of detergent contained. But we don’t have to worry about antibiotics-resistant bacteria. I’ve once heard a professor of bacteriology say, “Sterilization has no meaning because a colony of bacteria will soon grow again.” In may experience, disinfection was effective in many cases. (I aimed at suppressing bacteria growth as much as possible, not perfectly eliminating bacterium.)
Dr. Leung’s paper seems like documentation of a symposium or something like that and Discussion takes the form of questions and answers.
----- Excerpt -----
Andersen: Has anyone looked at replacing these strains with non-pathogens?
Leung: We looked at this many years ago but had concerns about producing a more severe infection. We restricted ourselves to strains which did not express protein A. Despite several attempts with such a strain, we never replaced the natural ones, in part because you needed too many bacteria. We were never able to replace the original organism.
----- End of excerpt -----
Some bacteriologist once seriously suggested that I replace S. aureus, which cannot be eliminated, with strains of low pathogenicity. I rejected her suggestion considering it too ethically difficult. Everybody seems to come up with a similar idea.
Note:
This is the plate agar I had used in the topical steroid withdrawal consultation. Culturing the plate after having pushed it against the patient’s epidermis will grow a white colony (on the yellow medium in case of staphylococcus aureus and on the red medium in case of staphylococcus epidermidis). The number of colonies is counted.
By the way, Dr. Takehara (Kanazawa University) says in his book that it is the wrong idea that response to steroids gets gradually poorer or steroids are ineffective for some patients (see Chapter 3 of Machigai-darake-no-atopi-chiryo, Many Misunderstandings for Atopic Dermatitis Treatment). I think this statement is wrong. It is true that it has been unknown till recently that superantigens generated by S. aureus are involved in steroid resistance. But this phenomenon has been clinically observed for decades. As mentioned in the previous chapter, there are many poor-response cases that are difficult to explain with steroid allergic contact dermatitis. To answer the patients’ inquiry for a poor response in this educational book, he should have referred to the possibility of steroid addiction due to too much use of corticosteroids, or an increased colony of S. aureus and been advised to consult the doctor. Neglecting steroid resistance caused by S. aureus and escalating the steroid potency in response to rash aggravation will just escalate steroid addiction.
As to measures against S. aureus, dermatologists supporting steroid withdrawal have different opinions about which measures to take:
1) Antibiotics;
2) Antiseptics; or
3) No measures.
I used to choose the second option and topically apply antiseptics (applying povidone-iodine to rinse away after 10 minutes, which is the method suggested by Dr. Sugimoto, Chiba University). I can accept option 3) but object choice 1) (application of antibiotics). Thorough sterilization is difficult, which is indicated in the reference material. In the first place, S. aureus adheres more readily to the AD patient’s skin because such patients cannot produce enough physiological antimicrobial substances such as HBD (human beta defensin) and antibiotics may induce resistant bacteria such as MRSA. MRSA leads to concurrent blood poisoning or limits the selection of antibiotics available as necessary and in some cases surgery is required for some reasons (e.g., retinal separation). There are physicians who prescribe antibiotics without hesitation at their clinics. Antibiotics might be effective in order to prevent patients from dropping out of the withdrawal regimen, but should be administered prudently.
Antiseptics cannot eliminate bacteria thoroughly either, and have the risk of developing contact dermatitis or destroying the skin barrier with a small amount of detergent contained. But we don’t have to worry about antibiotics-resistant bacteria. I’ve once heard a professor of bacteriology say, “Sterilization has no meaning because a colony of bacteria will soon grow again.” In may experience, disinfection was effective in many cases. (I aimed at suppressing bacteria growth as much as possible, not perfectly eliminating bacterium.)
Dr. Leung’s paper seems like documentation of a symposium or something like that and Discussion takes the form of questions and answers.
----- Excerpt -----
Andersen: Has anyone looked at replacing these strains with non-pathogens?
Leung: We looked at this many years ago but had concerns about producing a more severe infection. We restricted ourselves to strains which did not express protein A. Despite several attempts with such a strain, we never replaced the natural ones, in part because you needed too many bacteria. We were never able to replace the original organism.
----- End of excerpt -----
Some bacteriologist once seriously suggested that I replace S. aureus, which cannot be eliminated, with strains of low pathogenicity. I rejected her suggestion considering it too ethically difficult. Everybody seems to come up with a similar idea.
Note:
This is the plate agar I had used in the topical steroid withdrawal consultation. Culturing the plate after having pushed it against the patient’s epidermis will grow a white colony (on the yellow medium in case of staphylococcus aureus and on the red medium in case of staphylococcus epidermidis). The number of colonies is counted.
The below data of a patient show how the number of skin surface colony declines after disinfection.