Chapter 10 Result of 6-week Dermovate Application on Healthy Skin
Morphologic Investigations on the Rebound Phenomenon After Corticosteroid Induced Atrophy in Human Skin
By P Zheng, R M Lavker, P Lehmann and A M Kligman published in the J Invest Dermatol 82: 345-352 (1984)
This paper was prepared by a group at Pennsylvania University including Dr. Zheng (head) and Dr. Kligman.
Clobetasol propionate (Dermovate ointment known as the strongest topical corticosteroid in Japan) was topically applied on the forearm skin of 4 healthy volunteers twice a day for 6 weeks and then discontinued. For 2 subsequent weeks, which corresponds to the rebound period, the skin recovery was monitored histopathologically taking a skin sample.
Provided, however, that it is predicted inflammatory response was not visually observed during the rebound period, for there was no inflammatory cell infiltration observed pathologically.
However, with skin atrophy evident, this study endorses the theory proposed later by Dr. Cork, which is that long time topical steroid application makes proteases hyperactive and destroys corneodesmosome excessively, leading to severe inflammation of atopic dermatitis (rebound flare).
Though it seems to be just a case report for non-dermatologist doctors and general people who have had little chance to see skin pathology, it is rather shocking for dermatologists to see pathological change in healthy skin treated with topical Dermovate for six weeks.
Morphologic Investigations on the Rebound Phenomenon After Corticosteroid Induced Atrophy in Human Skin
By P Zheng, R M Lavker, P Lehmann and A M Kligman published in the J Invest Dermatol 82: 345-352 (1984)
This paper was prepared by a group at Pennsylvania University including Dr. Zheng (head) and Dr. Kligman.
Clobetasol propionate (Dermovate ointment known as the strongest topical corticosteroid in Japan) was topically applied on the forearm skin of 4 healthy volunteers twice a day for 6 weeks and then discontinued. For 2 subsequent weeks, which corresponds to the rebound period, the skin recovery was monitored histopathologically taking a skin sample.
Provided, however, that it is predicted inflammatory response was not visually observed during the rebound period, for there was no inflammatory cell infiltration observed pathologically.
However, with skin atrophy evident, this study endorses the theory proposed later by Dr. Cork, which is that long time topical steroid application makes proteases hyperactive and destroys corneodesmosome excessively, leading to severe inflammation of atopic dermatitis (rebound flare).
Though it seems to be just a case report for non-dermatologist doctors and general people who have had little chance to see skin pathology, it is rather shocking for dermatologists to see pathological change in healthy skin treated with topical Dermovate for six weeks.
1A: Control (before applying the topical steroid). Normal epidermis (E) shows basal (B), spinous (S), granular (G), and horny (H) layers. The horny layer is grown well displaying typical “basket-weave” appearance. Bar = 0.25 mm.
1B: Day 0 poststeroid. Viable epidermis (VE) is extremely thin and flattened with small cells having pyknotic nuclei. The granular layer has disappeared and the horny layer has lost “basket-weave”appearance.
1C: Day 2. Viable epidermis is increased in thickness with bigger cells of irregular sizes. Basal cells have larger nuclei. Melanocyte (M) has pyknotic nuclei and transparent cytoplasms.
1D: Day 4. Viable epidermis is thickened and has large irregular cells showing clear polarity (differentiation from basal to horny layer). Basal cells are bigger and cuboidal. Melanocytes are less conspicuous. Cell division (D) is active. The granular layer is prominent. The horny layer shows parakeratosis (persistence of the nuclei of keratinocytes). Clearance between cells is still wide (arrow).
1E: Day 7. Viable epidermis is markedly hyperplasitic with large cells containing well-defined nuclei. The horny layer, still showing parakeratosis, has begun to display the typical basket-weave appearance.
1F: Day14. Viable epidermis and granular layer are sill thicker than Control (1A), but horny layer has almost recovered to the normal state.
1B: Day 0 poststeroid. Viable epidermis (VE) is extremely thin and flattened with small cells having pyknotic nuclei. The granular layer has disappeared and the horny layer has lost “basket-weave”appearance.
1C: Day 2. Viable epidermis is increased in thickness with bigger cells of irregular sizes. Basal cells have larger nuclei. Melanocyte (M) has pyknotic nuclei and transparent cytoplasms.
1D: Day 4. Viable epidermis is thickened and has large irregular cells showing clear polarity (differentiation from basal to horny layer). Basal cells are bigger and cuboidal. Melanocytes are less conspicuous. Cell division (D) is active. The granular layer is prominent. The horny layer shows parakeratosis (persistence of the nuclei of keratinocytes). Clearance between cells is still wide (arrow).
1E: Day 7. Viable epidermis is markedly hyperplasitic with large cells containing well-defined nuclei. The horny layer, still showing parakeratosis, has begun to display the typical basket-weave appearance.
1F: Day14. Viable epidermis and granular layer are sill thicker than Control (1A), but horny layer has almost recovered to the normal state.
Electron micrograph of epidermis on Day 2.
The intercellular spaces between basal (B) and suprabasal (SB) cells are widened. The horny layer (H) is very thin. The granular layer (G) is one cell thick (there are only 3 layers of cells including the basal layer). Enlarged image at lower left shows high density of ribosomes (R) and absence of keratin filaments. Nucleus (N) has is finely chromatin. The intercellular space (I) is widened. D represents desmosomes.
The intercellular spaces between basal (B) and suprabasal (SB) cells are widened. The horny layer (H) is very thin. The granular layer (G) is one cell thick (there are only 3 layers of cells including the basal layer). Enlarged image at lower left shows high density of ribosomes (R) and absence of keratin filaments. Nucleus (N) has is finely chromatin. The intercellular space (I) is widened. D represents desmosomes.
The above pictures show the recovery sequence of the dermis. Glycosaminoglycans (mucopolysaccharide), died in blue with Hale’s colloidal iron stain, increase over time (A: Day 0; B: Day 2; C: Day 4; D: Day 7; E: Day 14)
Corticosteroid is targeted at fibroblasts in the dermis, and applying topical steroid reduces mucopolysaccharide (e.g., hyaluronan), which is produced by fibroblasts. Pictures A to E depict the progress of mucopolysaccharide recovery. Topical steroid leads to atrophy of dermis as well as epidermis.
Corticosteroid is targeted at fibroblasts in the dermis, and applying topical steroid reduces mucopolysaccharide (e.g., hyaluronan), which is produced by fibroblasts. Pictures A to E depict the progress of mucopolysaccharide recovery. Topical steroid leads to atrophy of dermis as well as epidermis.
8A is the picture of Control (before applying the topical steroid). 8B (Day 7) shows increased prominence of vessels (arrow), which is considered the change corresponding to epidermal hyperplasia during rebound. This is the change explaining capillary dilation, one of the side effects of topical corticosteroid.
Having been conducted on healthy subjects, inflammatory response was not seen and skin atrophy recovered soon. Atopic skin would have manifested strong inflammation in response to irritants.
Dr. Zheng belonged to Shanghai First Medical College when this paper was written in 1984. It seems he was studying at Pensylvania University then. I found that he currently runs his own clinic in Philadelphia specialized in internal medicine and surgery, not dermatology. I wonder if he has changed his specialty like me.
In fact, seeing strong side effects caused by topical steroids made me lose confidence to continue to work as a dermatologist. It is impossible to keep chronic eczema eruption suppressed by applying topical steroids for a long time without causing side effects at all.
I’m not saying atopic dermatitis (AD) is an incurable disease. It is not rare that AD is cleared naturally. In my experience, keeping environmental irritants at minimum leads to natural healing. However, this is not the result of medial practice such as medication by dermatologists. My impression is that there is not much that doctors can do for this disease. Alternative drugs such as calcineurin inhibitor are being developed though.
There might be other reasons for Dr. Zheng to have opened a non-dermatology clinic. But I’m sure he felt awful to find the topical steroid has such a big influence on the skin at the pathological tissue level, which cannot be confirmed visually.
Having been conducted on healthy subjects, inflammatory response was not seen and skin atrophy recovered soon. Atopic skin would have manifested strong inflammation in response to irritants.
Dr. Zheng belonged to Shanghai First Medical College when this paper was written in 1984. It seems he was studying at Pensylvania University then. I found that he currently runs his own clinic in Philadelphia specialized in internal medicine and surgery, not dermatology. I wonder if he has changed his specialty like me.
In fact, seeing strong side effects caused by topical steroids made me lose confidence to continue to work as a dermatologist. It is impossible to keep chronic eczema eruption suppressed by applying topical steroids for a long time without causing side effects at all.
I’m not saying atopic dermatitis (AD) is an incurable disease. It is not rare that AD is cleared naturally. In my experience, keeping environmental irritants at minimum leads to natural healing. However, this is not the result of medial practice such as medication by dermatologists. My impression is that there is not much that doctors can do for this disease. Alternative drugs such as calcineurin inhibitor are being developed though.
There might be other reasons for Dr. Zheng to have opened a non-dermatology clinic. But I’m sure he felt awful to find the topical steroid has such a big influence on the skin at the pathological tissue level, which cannot be confirmed visually.