A. Lassus
Helsinki Research Center, Stora Robertsgatan 8 A 1, FIN-00120 Helsinki, Finland

INTRODUCTION
Topical steroids are of proven therapeutic benefit but have a well recognized potential for side-effects, especially that of skin atrophy. Certainly within two weeks of starting treatment, and probably within a few days, microscopic degenerative changes may be seen in the epidermis with a reduction of cell size and the number of cell layers. These effects may be rapidly reversible but with chronic administration dermal changes become apparent. There is inhibition of the mitotic activity of fibroblasts resulting in reduction of collagen and glucosaminoglycan synthesis but probably the earliest evidence of dermal atrophy is a reduction in the diameter of the fibrils and then the collagen bundles become atrophic and separated. The latter effects have been reported to be caused by the inhibition of collagenase by steroids. (1) Elastin fibres in the upper layers of the dermis become thin and fragmented whereas those deeper down compact into a dense network. As a result of these atrophic changes, striae, teleangiectases, purpura and echymoses develop. Long-term use of potential steroids causes irreversible atrophy, while atrophy induced by short-term use may to some extent be reversible except for striae.

It has recently become evident that extracts from cartilage of marine fish, when used orally or topically (2,3,4) , have a strikingly good repairing effect on photodamaged and chronologically aged skin. It was therefore of interest to evaluate whether a prolonged systemic use of these compounds may have a repairing effect on severe atrophy of the skin due to long-term use of topical potential steroids.

PATIENTS
A total of 40 patients with severe atrophy of the skin due to long-term use of topical potential corticosteroids took part in the study (Table 1). Twenty-three patients were females and 17 males and 15 of them suffered from atopic dermatitis while 25 had chronic psoriasis of plaque type. All 40 had used Group III and 24 Group IV (Dermovate) for a mean period of 16 years (range 6-25 years). Symptoms and signs of skin atrophy were present on the extremities in all cases, on the face in 28 and on the trunk in 12 patients. Twelve suffered from some concomitant disease and eight were on concomitant medication. Prior to the study oral informed consent was obtained from all patients.

STUDY DESIGN
All patients were treated for eight months. The oral dose of Vivida depended on the body weight (2 tablets = 500 mg active substance daily if < 80 kg and 3 tablets = 750 mg active substance daily if > 80 kg). Patients using concomitant medication fore some other disease were allowed to continue with the same medication. The patients were also allowed to use emollient creams, but the use of corticosteroids, phototherapy etc. was not allowed during the treatment period.

Clinical evaluations were carried out at baseline and thereafter bimonthly for eight months. At each visit the following clinical parameters were evaluated from the same site on the dorsal surface of the forearm: thickness of the skin, laxity, dryness, purpura and echymoses, and teleangiectasia and graded as follows (0 = absent, 1 = mild, 2 = moderate and 3 = severe). At each visit the mean severity was calculated. In addition, a photograph was taken from the evaluated site and the epidermal and dermal thickness was measured with a Dermascan C scanner, and an elasticity index was determined with a Dermaflex A equipment (Cortex Ltd., Denmark). (5,6) An erythemal index was measured by the use of an Erythemal Meter (Diasthron Ltd., UK) (7) and the skin dryness was measured with a Corneometer (Corneometer CM 820, Courage + Khazaka, Germany).

Table 2.
Clinical evaluation of severity of symptoms and signs of skin atrophy at baseline and at end of treatment.

Clinical parameters	Mean severity at baseline	Mean severity at end of treatment
Decreased thickness of skin	2.95 (range 2-3)	0.00
Laxity	2.95 (range 2-3)	0.00
Purpura/Echymoses	2.25 (range 1-3)	0.00
Dryness	3.00	0.00
Teleangiectasia	2.33 (range 2-3)	0.98 (range 1-2)

Table 3.
Mean epidermal and dermal thickness, skin elasticity, erythemal and moisture indexes at baseline and after 8 months of treatment with Vivida of 40 patients with corticosteroid induced skin atrophy.

Parameters	Baseline	8 months
Epidermal thickness (mm)	0.11 (0.05-0.15)	0.28 (0.25-0.31)
Dermal thickness (mm)	0.80 (0.68-0.90)	1.55 (1.43-1.78)
Elasticity Index	44 (39-53)	74 (65-78)
Erythemal Index	0.391 (0.300-0.490)	0.224 (0.150-0.290)
Moisture Index	27.6 (11-37)	83.7 (75-97)

STATISTICAL ANALYSIS
Statistical methods were applied to continuous as well as categorical data collected during the study. Categorical data variables were analysed with a standard x-test for homogenity and Fischer's exact test was also used. Results were regarded statistically significant if the corresponding p-value was < 0.05 and marginally significant if the p-value was higher or equal to 0.05 but lower or equal to 0.10.

RESULTS
The results of treatment are presented in Table 2. At baseline skin atrophy was present on the lower part of the extremities in all patients, in the face in 28 patients and on the trunk in 12 patients. Seven of the latters had also striae. One site of the back of the forearm was clinically evaluated throughout the study. As shown in Table 2 the mean decrease of skin thickness was severe at baseline (2.95) as well as laxity (2.95). Purpura and echymosis were also severe (2.25) as well as teleangiectasia (2.33). All patients had severely dry skin (3.00). After eight months of treatment skin thickness and elasticity were evaluated as normalized in all patients as was also dryness. Purpura or echymosis could not be observed, but all patients showed increased pigmentation. Teleangiectasia had decreased significantly from mean 2.33 to 0.98. The treatment had only minor effect on striae. Ultrasound measurement as well as determination of erythemal and Corneometer Indexes (Table 3). The mean thickness of epidermis had increased from 0.11 mm to 0.28 mm, the mean thickness of dermis from 0.80 mm to 1.55 mm and the mean Erythemal index had decreased from 0.391 to 0.224, and the Corneometer Index had increased from 27.6 to 83.7. These findings confirm well the clinical evaluations. The atopic dermatitis was completely cured after 4-6 months of treatment in all patients and 11 of the patients with psoriasis experienced a significant improvement of their skin symptoms and signs after the treatment period.

No adverse effects were reported by the patients or observed by the investigator during the study period.

DISCUSSION
The structural changes and the signs and symptoms of chronologically aged skin and those of corticosteroid induced chronic atrophy of the skin are partially very similar. Thinning of epidermis and laxity as well as dryness, purpura and echymoses occur in both conditions. However, in chronologically aged skin striae are not observed, while in corticosteroid atrophy premalignant or malignant tumours are seldom observed. Previously it has been shown that Vivida has a good reconstructive effect on chronologically and sun-damaged skin. The treatment period was rather short in the earlier studies, because a rapid effect could be expected. As the changes in both epidermis and dermis in corticosteroid induced atrophy are severe and comparative to those observed in old age, it was decided that a long treatment period would probably be necessary in the present trial. This proved to be true, since improvement was much slower in patients with atrophy caused by topical corticosteroids as compared with patients with chronologically or sun-damaged skin in the age group 40-60 years.

However, an eight-month treatment with Vivida cured most symptoms and signs completely in patients with corticosteroid atrophy. The therapy was less effective as regards striae and teleangiectasia, although the latter showed significant response.

This trial confirmed observations seen in praxis that Vivida has a very good effect on atopic dermatitis (obviously due to the moisturizing effect) and to some extent also on skin symptoms in patients with psoriasis, probably due to an effect on the disturbed cell metabolism in these patients.

The mechanism by which the marine derived polysaccharides, which are the active ingredients in Vivida, corrects skin damages of different types, is still hypothetical. It is well known that the active substances have an affinity only to skin tissue and blood vessel walls. They may stimulate fibroblast activity as well as regulate the metabolism of the basal cell layer. It has been shown that Vivida also has an activating effect on hair and nail growth as well as on the activity of sebaceous glands, which can cause greasiness of the skin and transient mild acne.

In conclusion, the present study indicated that a prolonged use of orally administered Vivida has a good effect on permanent corticosteroid induced atrophy of the skin.

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