Chapter 3 Reports in Japan – 1
Steroid Withdrawal Syndrome by Topical Corticosteroid
By Mitsukuni Enomoto, Seiji Arase, Fumio Shigemi, Katsuyuki Takeda published in the Journal of Japanese Cosmetic Science Society, Vol.15, No.1(1991)
This is the first paper in Japan that covered skin conditions manifested during the rebound phase after the topical corticosteroid withdrawal. Cited below is the whole part of the Abstract, which is very interesting.
----- Excerpt -----
Corticosteroid withdrawal syndrome, the systemic side effect, occurred in 7 patients who had used potent topical corticosteroids for a long time on their skin lesions. In all cases, characteristic symptoms of the syndrome such as weakness, fatigue, low grade fever, oligouria, tachycardia, gastrointestinal and psychological symptoms were noted. In addition, diffuse edematous erythema appeared widely beyond the primary lesions about 5 days after cessation of the drugs.
These symptoms, together with the facts that adreno-cortical insufficiency was found in 5 of 7 patients and either systemic corticosteroid or ACTH was requested for the treatment in all patients, lead us to consider that the erythema was not flare of the primary diseases but was a rebound skin manifestation in the corticosteroid withdrawal syndrome.
Local withdrawal rebound eruption frequently occurs on the face which is now well known as rosacea-like dermatitis, but a systemic one caused by topical corticosteroid as mentioned here has not been reported.
It should be noted that topical corticosteroids can induce the withdrawal syndrome, and diffuse rebound erythema is a characteristic skin manifestation of the conditions as mentioned here which are caused by topical corticosteroids.
---- End of excerpt -----
This paper was contained in the Journal of Japanese Cosmetic Science Society, which had been unfamiliar to me. Indicated below is a part of the table of contents.
Volume 15, No. 1
Table of Contents
Original articles:
1. Review of DS-2630 ointment’s effects on serum cortisol level and general clinical laboratory test measurements – comparison with 0.064% betamethasone dipropionate ointment used for healthy subjects (by Mitsukuni Enomoto, Seiji Arase, Katsuyuki Takeda) … 6
2. Steroid Withdrawal Syndrome by Topical Corticosteroid (by Mitsukuni Enomoto, Seiji Arase, Fumio Shigemi, Katsuyuki Takeda) … 17
(snip)
Conference reports:
Reports on the 15th Conference of Japanese Society for Contact Dermatitis and 40th Conference of Japanese Society for Dermatoallergology (by Ritsuko Hayakawa) … 45
This paper was released together with the clinical trial report on a new topical steroidal cream under development then. Coauthor Dr. Takeda was engaged in the research of various kinds of topical steroids in those days. The magazine also contains the conference reports of the Japanese Society for Contact Dermatitis and the Japanese Society for Dermatoallergology, for it was not rare for those societies without their own magazines to publish their conference or clinical trial reports in magazines that seemed irrelevant to them.
Though the magazine itself seems to have little relation with dermatology, the present paper, coauthored and naturally authorized by Dr. Takeda having been actively engaged in many clinical trials of topical corticosteroids, is considered authoritative. It is also interesting and ironical this paper was published together with a clinical trial report on the topical corticosteroid.
Complement:What can be read from the clinical trial report on topical steroids
A clinical trial report is a sort of proof that a given medicine is effective for certain diseases and symptoms. Any medicine will be evaluated for effectiveness before commercial release and reevaluated after release in the form of follow-up investigation. Such evaluation results will be reported as clinical trial reports on the medical or other magazines.
I once wondered and investigated to what extent these reports confirm the safety for long-term topical steroid use. The data shown below is the results of this investigation.
”Long-term (prolonged) use” generally means the use for up to 120~130 days.
In the report titled “Topical and systemic effects of long-term application of diflorasone diacetate,” 1) for example, the maximum observation period was 16 weeks. As to the report titled “Clinical usability (clinical effect and systemic influence) of halcinonide when topically applied for a long time,” 2) observation periods were 14 to 112 days (59 days in average).
The report titled “Usability review of halcinonide ointment when topically applied for a long time” 3) studied 3 cases of atopic dermatitis (AD) for the periods ranging from 35 to 127 days. I could find only these 3 reports employing more than 100 days of observation period, and others judged the usability with topical application duration of 1 to 5 weeks.
“Guideline for Topical Corticosteroid Development” (private plan by Ishihara)3) recommended the third phase test duration of 1 to 3 weeks and long-term application test period of 1 to 3 months.
In treating AD, it is not rare that the topical corticosteroid application period extends a few years to decades. In spite of this fact, clinical trial or follow-up investigation after actual use does not ensure safety for such prolonged application. Additionally, papers covering long time administrations only pay attention to the deterioration of pituitary-adrenal function and do not check for steroid addiction or recurrence of severe inflammation after discontinuation or dose reduction (rebound phenomenon).
There exist no clinical trial reports reviewing steroid addiction or recurrence of severe inflammation after discontinuation or dose reduction (rebound phenomenon)
Some medicines induce addiction and the others don’t. A hypertension pill, for example, does not lose its effectiveness nor require dose increase over a long time use. There occurs no strong symptom rebound after discontinuation or dose reduction.
However, topical corticosteroid applied on the skin induces addiction, which I have warned repeatedly. Such medicines must be prescribed with special care, e.g., inserting drug holidays regularly instead of using continuously to prevent addiction. I’d just like to say physicians should consider how to administer medicines to prevent addiction. I do not intend to totally deny topical corticosteroid application.
While investigating clinical trial reports, I found the statement implying the rebound phenomenon. Harada et al 5) prescribed less potent betamethasone valerate for 21 AD patients who had been led to remission after 1 to 4-week application of clobetasol propionate. As a result, the remission was maintained in 13 patients, whereas recurrence of flare was observed in 8 (38%). They also found the statistically significant fact that patients with remaining papular(including prurigo nodularis)were likely to suffer from recurrence of inflammation.
For clinicians supporting the topical corticosteroid (TCS) withdrawal, it is not uncommon that many AD patients with prurigo nodularis under prolonged TCS treatment manifest rebound flare after TCS discontinuation, which will turn into erythroderma and disappear naturally. It is likely that Harada et al were observing the rebound phenomenon through the cases of recurred inflammation.(This report was written in 1989, two years before Enomoto et al released the paper in the Journal of Japanese Cosmetic Science Society.)
Harada et al. wrote in the Discussion that higher performance may be gained by tapering steroid potency in smaller steps from strongest, very strong, strong, mild to weak based on good results as high as 62% achieved when drug potency was directly lowered from the strongest to strong. Remission rate is considered higher in tapering from the strongest to very strong than in tapering the strongest to strong. How much higher is it? Suppose remission rate in tapering from the strongest to very strong is 81%, which is an intermediate value between 100 and 62, and that in tapering from very strong to strong is also 81%. Then, the remission rate in tapering from the strongest to strong can be calculated as 0.81×0.81=0.66, and there is not so much difference between leveling down in 2 steps and directly. Assuming remission rate in tapering from strong to weak and from weak to steroid-off are 62% respectively. The final remission rate will be calculated as 0.62×(0.62×0.62)=0.24. That is to say, 3 out of 4 will suffer from inflammation recurrence at a certain phase and cannot evade rebound flare after TCS discontinuation.
Tapered withdrawal may be effective for splitting up the rebound phenomenon, but it can’t theoretically remove the chance of rebound. It is a fantasy that the tapering method can achieve steroid withdrawal while keeping the skin cleared of rash. The Japanese Dermatological Association’s current guideline instructs doctors to use more potent steroids when flare gets worse and less potent ones in remission. As long as the present guideline is applied, addictive patients never get out of addiction. It should be revised as follows: “When the eruption is suspected to be induced by steroid addiction, a wait-and-see approach should be taken without escalating steroid potency and amount even if the rash is temporarily aggravated.
The above calculation also indicates 24% (1 out of 4) can withdraw from TCS without rebound, whatever method may be taken. It is considered that such patients have not fallen into addiction in spite of topical steroid application. In my experience, there were cases of successful steroid withdrawal with little rebound.
1)Diflorasone diacetate research team, Western Japan Division of JDA 47:530、1985
2)Halcinonide long-term clinical study team, JPT 12:1815、1984
3)Norimasa Hara et al, JPT 12:4871、1984
4)Shotaro Harada, Japanisch-Deutsche Medizinisch Beriche 38:33、1993
5)Shotaro Harada et al, Japanese Society of Pediatric Dermatology 8(sup)137、1989
The above-mentioned paper by Dr. Enomoto et al. is very precious as it reported on the systemic rebound phenomena after TCS discontinuation. However, he used systemic steroids for treatment and did not mention whether or not patients had finally succeeded in withdrawing from steroids. What happened in 1991 was that some dermatologists at last began to notice the existence of steroid addiction-specific development of eruptions.
It was in 1952, when Dr. Sulzburger reported that topical steroids are effective to alleviate the flare of AD. What was used then was hydrocortisone acetate, which was approved in 1953 in Japan.
Clobetasol propionate, classified into the strongest steroids, was authorized in 1978 in Japan. As the paper by Dr. Enomoto et al. was published in 1991, it was 37 years after hydrocortisone acetate approval and 13 years after cobetasol propionate approval that rebound flare different from the primary skin disorder was officially reported for the first time in Japan.
Steroid Withdrawal Syndrome by Topical Corticosteroid
By Mitsukuni Enomoto, Seiji Arase, Fumio Shigemi, Katsuyuki Takeda published in the Journal of Japanese Cosmetic Science Society, Vol.15, No.1(1991)
This is the first paper in Japan that covered skin conditions manifested during the rebound phase after the topical corticosteroid withdrawal. Cited below is the whole part of the Abstract, which is very interesting.
----- Excerpt -----
Corticosteroid withdrawal syndrome, the systemic side effect, occurred in 7 patients who had used potent topical corticosteroids for a long time on their skin lesions. In all cases, characteristic symptoms of the syndrome such as weakness, fatigue, low grade fever, oligouria, tachycardia, gastrointestinal and psychological symptoms were noted. In addition, diffuse edematous erythema appeared widely beyond the primary lesions about 5 days after cessation of the drugs.
These symptoms, together with the facts that adreno-cortical insufficiency was found in 5 of 7 patients and either systemic corticosteroid or ACTH was requested for the treatment in all patients, lead us to consider that the erythema was not flare of the primary diseases but was a rebound skin manifestation in the corticosteroid withdrawal syndrome.
Local withdrawal rebound eruption frequently occurs on the face which is now well known as rosacea-like dermatitis, but a systemic one caused by topical corticosteroid as mentioned here has not been reported.
It should be noted that topical corticosteroids can induce the withdrawal syndrome, and diffuse rebound erythema is a characteristic skin manifestation of the conditions as mentioned here which are caused by topical corticosteroids.
---- End of excerpt -----
This paper was contained in the Journal of Japanese Cosmetic Science Society, which had been unfamiliar to me. Indicated below is a part of the table of contents.
Volume 15, No. 1
Table of Contents
Original articles:
1. Review of DS-2630 ointment’s effects on serum cortisol level and general clinical laboratory test measurements – comparison with 0.064% betamethasone dipropionate ointment used for healthy subjects (by Mitsukuni Enomoto, Seiji Arase, Katsuyuki Takeda) … 6
2. Steroid Withdrawal Syndrome by Topical Corticosteroid (by Mitsukuni Enomoto, Seiji Arase, Fumio Shigemi, Katsuyuki Takeda) … 17
(snip)
Conference reports:
Reports on the 15th Conference of Japanese Society for Contact Dermatitis and 40th Conference of Japanese Society for Dermatoallergology (by Ritsuko Hayakawa) … 45
This paper was released together with the clinical trial report on a new topical steroidal cream under development then. Coauthor Dr. Takeda was engaged in the research of various kinds of topical steroids in those days. The magazine also contains the conference reports of the Japanese Society for Contact Dermatitis and the Japanese Society for Dermatoallergology, for it was not rare for those societies without their own magazines to publish their conference or clinical trial reports in magazines that seemed irrelevant to them.
Though the magazine itself seems to have little relation with dermatology, the present paper, coauthored and naturally authorized by Dr. Takeda having been actively engaged in many clinical trials of topical corticosteroids, is considered authoritative. It is also interesting and ironical this paper was published together with a clinical trial report on the topical corticosteroid.
Complement:What can be read from the clinical trial report on topical steroids
A clinical trial report is a sort of proof that a given medicine is effective for certain diseases and symptoms. Any medicine will be evaluated for effectiveness before commercial release and reevaluated after release in the form of follow-up investigation. Such evaluation results will be reported as clinical trial reports on the medical or other magazines.
I once wondered and investigated to what extent these reports confirm the safety for long-term topical steroid use. The data shown below is the results of this investigation.
”Long-term (prolonged) use” generally means the use for up to 120~130 days.
In the report titled “Topical and systemic effects of long-term application of diflorasone diacetate,” 1) for example, the maximum observation period was 16 weeks. As to the report titled “Clinical usability (clinical effect and systemic influence) of halcinonide when topically applied for a long time,” 2) observation periods were 14 to 112 days (59 days in average).
The report titled “Usability review of halcinonide ointment when topically applied for a long time” 3) studied 3 cases of atopic dermatitis (AD) for the periods ranging from 35 to 127 days. I could find only these 3 reports employing more than 100 days of observation period, and others judged the usability with topical application duration of 1 to 5 weeks.
“Guideline for Topical Corticosteroid Development” (private plan by Ishihara)3) recommended the third phase test duration of 1 to 3 weeks and long-term application test period of 1 to 3 months.
In treating AD, it is not rare that the topical corticosteroid application period extends a few years to decades. In spite of this fact, clinical trial or follow-up investigation after actual use does not ensure safety for such prolonged application. Additionally, papers covering long time administrations only pay attention to the deterioration of pituitary-adrenal function and do not check for steroid addiction or recurrence of severe inflammation after discontinuation or dose reduction (rebound phenomenon).
There exist no clinical trial reports reviewing steroid addiction or recurrence of severe inflammation after discontinuation or dose reduction (rebound phenomenon)
Some medicines induce addiction and the others don’t. A hypertension pill, for example, does not lose its effectiveness nor require dose increase over a long time use. There occurs no strong symptom rebound after discontinuation or dose reduction.
However, topical corticosteroid applied on the skin induces addiction, which I have warned repeatedly. Such medicines must be prescribed with special care, e.g., inserting drug holidays regularly instead of using continuously to prevent addiction. I’d just like to say physicians should consider how to administer medicines to prevent addiction. I do not intend to totally deny topical corticosteroid application.
While investigating clinical trial reports, I found the statement implying the rebound phenomenon. Harada et al 5) prescribed less potent betamethasone valerate for 21 AD patients who had been led to remission after 1 to 4-week application of clobetasol propionate. As a result, the remission was maintained in 13 patients, whereas recurrence of flare was observed in 8 (38%). They also found the statistically significant fact that patients with remaining papular(including prurigo nodularis)were likely to suffer from recurrence of inflammation.
For clinicians supporting the topical corticosteroid (TCS) withdrawal, it is not uncommon that many AD patients with prurigo nodularis under prolonged TCS treatment manifest rebound flare after TCS discontinuation, which will turn into erythroderma and disappear naturally. It is likely that Harada et al were observing the rebound phenomenon through the cases of recurred inflammation.(This report was written in 1989, two years before Enomoto et al released the paper in the Journal of Japanese Cosmetic Science Society.)
Harada et al. wrote in the Discussion that higher performance may be gained by tapering steroid potency in smaller steps from strongest, very strong, strong, mild to weak based on good results as high as 62% achieved when drug potency was directly lowered from the strongest to strong. Remission rate is considered higher in tapering from the strongest to very strong than in tapering the strongest to strong. How much higher is it? Suppose remission rate in tapering from the strongest to very strong is 81%, which is an intermediate value between 100 and 62, and that in tapering from very strong to strong is also 81%. Then, the remission rate in tapering from the strongest to strong can be calculated as 0.81×0.81=0.66, and there is not so much difference between leveling down in 2 steps and directly. Assuming remission rate in tapering from strong to weak and from weak to steroid-off are 62% respectively. The final remission rate will be calculated as 0.62×(0.62×0.62)=0.24. That is to say, 3 out of 4 will suffer from inflammation recurrence at a certain phase and cannot evade rebound flare after TCS discontinuation.
Tapered withdrawal may be effective for splitting up the rebound phenomenon, but it can’t theoretically remove the chance of rebound. It is a fantasy that the tapering method can achieve steroid withdrawal while keeping the skin cleared of rash. The Japanese Dermatological Association’s current guideline instructs doctors to use more potent steroids when flare gets worse and less potent ones in remission. As long as the present guideline is applied, addictive patients never get out of addiction. It should be revised as follows: “When the eruption is suspected to be induced by steroid addiction, a wait-and-see approach should be taken without escalating steroid potency and amount even if the rash is temporarily aggravated.
The above calculation also indicates 24% (1 out of 4) can withdraw from TCS without rebound, whatever method may be taken. It is considered that such patients have not fallen into addiction in spite of topical steroid application. In my experience, there were cases of successful steroid withdrawal with little rebound.
1)Diflorasone diacetate research team, Western Japan Division of JDA 47:530、1985
2)Halcinonide long-term clinical study team, JPT 12:1815、1984
3)Norimasa Hara et al, JPT 12:4871、1984
4)Shotaro Harada, Japanisch-Deutsche Medizinisch Beriche 38:33、1993
5)Shotaro Harada et al, Japanese Society of Pediatric Dermatology 8(sup)137、1989
The above-mentioned paper by Dr. Enomoto et al. is very precious as it reported on the systemic rebound phenomena after TCS discontinuation. However, he used systemic steroids for treatment and did not mention whether or not patients had finally succeeded in withdrawing from steroids. What happened in 1991 was that some dermatologists at last began to notice the existence of steroid addiction-specific development of eruptions.
It was in 1952, when Dr. Sulzburger reported that topical steroids are effective to alleviate the flare of AD. What was used then was hydrocortisone acetate, which was approved in 1953 in Japan.
Clobetasol propionate, classified into the strongest steroids, was authorized in 1978 in Japan. As the paper by Dr. Enomoto et al. was published in 1991, it was 37 years after hydrocortisone acetate approval and 13 years after cobetasol propionate approval that rebound flare different from the primary skin disorder was officially reported for the first time in Japan.