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Clinical aspects of glucocorticoid treatment

Kristian Thestrup-Pedersen

BACKGROUND

The first report on the efficacy of topical steroids became available in 1952, when compound F (i.e. hydrocortisone) was documented to be effective in various dermatoses including the treatment of atopic eczema.1 Five decades of clinical documentation and the experience of many doctors have proven the usefulness of topical steroids, which together with emollients today still are the 'gold standard' of treatment for atopic eczema. Although hundreds of trials have shown their efficacy, most have been limited to a treatment period of up to 4 weeks, and long-term trials are remarkably few.

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BIOCHEMISTRY OF STEROIDS

Any topical steroid needs to have a few basic characteristics of its molecule, which stems from the cholesterol ring (Figure 15.1). The position on the molecule of double bonds and various side chains has a major impact on their biological efficacy. The 'gluco-corticoid effect' versus the 'mineralo-corticoid effect' also depends upon the presence of double bonds and side chains. As an example all topical steroids must have a hydroxyl (-OH) group at position 11 as they are inactive without. A double bond between 1 and 2, fluorination at position 9, and modifications of the side chains in 16,17 position bring increased potency to the molecule. The most recently marketed products all have their side chains at the 16 or 17 position removed at first passage through the liver, therefore -in theory - having less systemic effects than molecules, where the side chains are not removed.

Figure 15.1 The steroid molecule used for topical steroids.

The potency of steroids is based on their vasoconstriction capacity2 combined with their clinical effect. Topical steroids are listed into 4 groups, ranging from mild potency, i.e. hydrocortisone acetate 1%, through moderate and potent to very potent steroids.3 A listing of these groups can be found in various pharmacological manuals.

ACTIONS OF TOPICAL STEROIDS Anti-inflammatory effects

Steroids are effective in eczema, because they have a broad spectrum of activity on the inflammation creating

Table 15.1 A listing of anti-inflammatory effects of topical steroids

• A broad anti-inflammatory effect on T lymphocytes through a blockade of the release of cytokines leading to the almost immediate diminishing of itch, which is probably cytokine mediated

• Blocking of dendritic cells in antigen presentation and their removal from epidermis and dermis

• Blocking and removal of mast cells from the skin

• Down-regulation of chemokine receptors on inflammatory cells

• Down-regulation of adhesion molecules inhibiting cellular emigration to the skin

• Vasoconstriction inhibiting migration of T cells and eosinophils

• Inhibition of other mediator cascades (prostaglandins, leukotrienes)

eczema. Table 15.1 lists a number of effects which will improve the eczema.

All these effects have a 'shot-gun' effect on the skin inflammation. In addition, the effects come quickly as steroid molecules are easily absorbed into the skin.

Absorption of steroids in different anatomical regions

An important study looked at the absorption of 3H-labelled hydrocortisone acetate in various regions of the body in healthy volunteers.4 If absorption through the skin on the volar aspect of the forearm was used as 'standard', it was observed that the absorption of steroids on scrotal skin was 42 x higher, on face 6-8 x higher and in palms 0.2 x higher (or 5-fold lower). Thus, absorption varies depending on the anatomical region, something which should be considered when prescribing topical steroids.

Absorption of steroid is increased when the skin barrier is disrupted as it is in patients with atopic eczema. Thus, plasma cortisol levels became increased even after application of hydrocortisone acetate. When the skin barrier is repaired the absorption falls.5,6

EFFICACY, DOSING, DURATION, AND AMOUNT OF STEROIDS TO BE USED

Efficacy

Figure 15.2 a,b shows a 14-months-old child before and 1 week after treating his eczema once daily with

Steroid Taper Old
Figure 15.2 A 14-month-old child (a) before and (b) 1 week after treating the eczema with a topical steroid.

mometasone furoate. The pictures illustrate what is known from daily practice: topical steroids clear eczema and they do so fast.

Table 15.2 lists the outcome of a recent study documenting how the majority of patients aged 12-65 years and with atopic eczema can control their eczema using fluticasone propionate and how they, on a long-term basis, can prevent a relapse through twice weekly application of steroid on previously treated areas.

Patients were treated daily for 4 weeks to induce remission, when 9% discontinued because of lack of effect. The remaining patients (91%) were eligible for maintenance treatment. Note how prophylactic treatment keeps

Table 15.2 Atopic eczema control by patients aged 12-65 years old using fluticasone propionate twice weekly

Maintenance treatment

Fluticasone cream 0.05% twice weekly + emollient

Placebo cream daily

Number of patients

70

84

Outcome after 16 weeks Relapse 19% No relapse 81%

64% 36%

81% without eczema for a 4-month period; note too that emollients are able to keep one-third of the patients in remission over a 16-week period.7

Dosing

Infants

Infants, at the moment, only have steroids registered as an anti-inflammatory topical treatment for eczema. They work well, and if the eczema is mild to moderate, low potency topical steroids like hydrocortisone acetate or hydrocortisone butyrate will be highly effective in many children. Following remission of eczema, emollients can for a certain time keep the skin normal and the steroid can be applied again for a short course, if symptoms of eczema relapse. However, the quite extensive steroid phobia among parents often leads to a lack of compliance.8

Children and adults

Children and adults with severe eczema often need the advantage of the quick effects on symptom relief from potent topical steroids. Following remission less potent steroids can be used or intermittent treatment can be initiated for long-term control.7 It seems equally effective to use short bursts of a potent topical corticos-teroid versus prolonged use of a mild preparation in children with mild to moderate atopic eczema.9

Application frequency and duration of treatment

A few studies show that application once daily is as effective as twice daily for the same steroid.10 This author therefore recommends that emollients are used in the morning as itch is less present in the morning hours, but when the child becomes tired in the afternoon, bouts of itching occur and steroids should then be applied. Emollients are steroid-sparing,11 maybe because the stratum corneum acts as a reservoir for steroids and application of emollients induces a steroid release.12

A recent survey on topical steroids and their use in atopic eczema underlines that we are lacking comparative studies on different steroids for the various forms of atopic eczema and especially how to use steroids for long-term control.13

Amount of steroids to be used for eczema treatment

The 'fingertip unit' was introduced as a practical and instructive way of dosing the amount of steroid which is relevant for the various anatomical regions.14,15 Table 15.3 shows the recommended maximal use of mild to moderate topical steroid per week according to the age of the child. If potent steroids are used it is recommended to use half the amount only. The amounts are based on how much is needed if all skin was affected by eczema, and the steroid was applied once daily.

Wet dressing

This dosing of steroids is very effective for children with severe, often oozing eczema.16 The reason is that wet dressings leave a cooling effect on the skin, leading to relief of itch. At the same time steroid absorption is dramatically increased. Wet dressings have a further drawback, as they are a very time-consuming way of applying steroids, often requiring an experienced nurse. They should be restricted for severe cases only and for short-term treatment: i.e. a maximum of 2 weeks.

Dispensary forms

Steroids are easy to dissolve; therefore they can be applied in ointments, which are good for dry skin and lead to improved absorption of the steroid. Creams are better for oozing eczema and where the occlusive effects of ointments are counterproductive for a normal transepidermal water evaporation. Creams are cosmet-ically much more acceptable for the patient. For hairy body areas, gels or lotions are the best way for an easy application of steroid. The dispensary forms of topical steroids are therefore optimal.

Combinations with antiseptics or antibiotics

There are many products on the market combining a topical steroid with antibacterial and antifungal drugs.

Table 15.3 Recommended weekly cumulative use of steroid according to age

Age 3 months 6 months 12 months 2 years 3 years 5 years 7 years 10 years 12 years

Grams 28 33 42 47 56 70 86 100 100

The role of Staphylococcus aureus and its secretion of superantigens, and the possible role of Pityrosporoum ovale for head and neck dermatitis (HNAD) has been considered. There are well-conducted studies showing that addition of Fucidin (fusidic acid) to hydrocortisone led to a significantly quicker remission of atopic eczema during the initial 2 weeks of treatment,17 but other studies using a different antiseptic are not able to support this finding.18,19 It is known that topical steroids themselves will reduce the number of S. aureus on the skin, when the eczema is cleared.20 However, addition of a soap with 1.5% triclocarban acting against S. aureus led to a significant reduction in eczema activity.21 Addition of an antifungal compound (ketoconazole) to hydrocortisone cream could however not give a significant beneficial effect in the treatment of HNAD in adults.22 Systemic antibiotics over a 4-week period did not change the activity of atopic eczema.23 The Health Assessment Report does therefore not at the moment recommend use of a combinatory treatment with topical steroids and antimicrobials, neither topically nor systemically.13 However, it is a fact that many of these products are used by doctors. Recent observations from the UK could indicate that using such products should be only initially to avoid the risk of resistance development.24

DURATION OF TREATMENT INCLUDING PROPHYLACTIC USE OF TOPICAL STEROIDS

Topical steroids will within a treatment period of 4 weeks either completely clear or significantly reduce the eczema activity.7,9 Many parents or patients therefore stop treatment as eczema has gone and they are afraid of side effects. On continuing with emollients one-third of patients can stay clear of eczema for up to 4 months,7 but the 'prophylactic use' of topical steroids has now become established as an efficient and economical way of keeping atopic eczema under con-trol.7,25,26 There seem to be very few clinical side effects from using potent topical steroid twice weekly except in the face and genital regions, where hydrocortisone is recommended. One study measured skin thickness using ultrasound and observed that 10% of the patients did develop some skin atrophy.9

SIDE EFFECTS INCLUDING CONTACT ALLERGY

A list of potential side effects is shown below:

• Skin atrophy through atrophy of epidermis and disruption of collagen and elastic fibres in dermis leading to potential development of striae distensae (Figure 15.3).

• Skin vessel fragility leading to teleangiectasia and bleeding, especially seen in elderly patients, but rarely in children (Figure 15.4).

• Systemic absorption with increase of plasma cortisol and a potential risk of HPA disturbance; especially seen during the initial days of eczema treatment because of disrupted skin barrier.

• Inhibition of melanocyte activity, which in some patients will lead to hypopigmentation.

• Iatrogenic dermatitis caused by excessive use of topical steroid with a relatively too high 'efficacy' e.g. hypertrichosis, steroid acne, perioral dermatitis, tinea incognito, pustular psoriasis.

The side effects can be evident within 1 week of treatment as seen by diminished skin thickness on ultrasound investigation. Side effects are much more common among elderly patients. They rarely occur in children with atopic eczema, when properly used. The reason for side effects is that collagen synthesis is inhibited27 with a diminished elasticity and increased fragility of the various structures in the skin.

Adrenal function and plasma cortisol levels

All topical steroids are absorbed through the skin and even treatment with hydrocortisone acetate in active atopic eczema will lead to increased plasma cortisol levels.5,6 However, it has been shown that the adrenal function is normal after topical steroids.28-30 There was no growth inhibition of children during a 2-week treatment of children with a potent topical steroid; actually the removal of eczema led to catch-up growth, i.e. a significant increase of the growth rate in children after controlling the eczema.31 Most children relapsed within 2 weeks, indicating the need for long-term treatment strategies.

Severe Striae
Figure 15.3 Striae distensae following longterm usage of potent topical steroid.
Topical Dermatitis
Figure 15.4 Ecchymoses in an elderly lady following longterm usage of potent topical steroid.

The use of topical steroids during pregnancy does not bring risks for the child.32 This was concluded as pregnant women on systemic steroids because of asthma did not have increased risks regarding their child.

Contact allergy to topical steroids

Contact allergy to topical steroids is by some investigators claimed to occur in up to 4% of all atopic eczema patients.33 However, in Denmark the prevalence of contact eczema is around 1%.34 Eczema not responding to topical steroids should be investigated for eventual steroid contact allergy. Reading of the tests should include a 7-day reading.

USE OF SYSTEMIC STEROIDS

There is a surprising lack of use of systemic steroids in atopic eczema.35 The reason are the side effects including the possibility of osteoporosis. Some parents or patients lack sufficient insight into their disease often accompanied by a relative lack of compliance leading to insufficient eczema control. If so, a low dose of systemic steroids can be used for some months. Likewise, an acute severe flare may be cured with a short-term intensive systemic dose, e.g. 40 mg prednisolone for 1 week, and then a reduction over a couple of weeks.

THE FUTURE OF STEROIDS

Although the new calcineurin inhibitors are now available with their advantages of being effective, specific, and without the side effects of steroids, there surely is a future for topical steroids in atopic eczema. The steroids are here to stay. The future will show how the two different topical compounds are used. This author recommends the use of steroids in the acute phase (see Figure 15.2 a,b), but then switching to topical cal-cineurin inhibitors for long-term control.

REFERENCES

1. Sultzberger MB, Witten VH. The effect of topically applied compound F in selected dermatoses. J Invest Dermatol 1952; 19: 101-2.

2. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs 1988; 36 (Suppl 5): 51-61.

3. Poulsen J, Rorsman H. Ranking of glucocorticoid creams and ointments. Acta Derm Venereol 1980; 60: 57-60.

4. Maibach HI. In vivo percutaneous penetration of corticoids in man and unresolved problems in their efficacy. Dermatologica 1976; 152(Suppl 1): 11-25.

5. Turpeinen M, Salo OP, Leisti S. Effect of percutaneous absorption of hydrocortisone on adrenocortical responsiveness in infants with severe skin disease. Br J Dermatol 1986; 115: 475-84.

6. Turpeinen M, Mashkilleyson N, Bjorksten F, Salo OP. Percutaneous absorption of hydrocortisone during exacerbation and remission of atopic dermatitis in adults. Acta Derm Venereol 1988; 68: 331-5.

7. Berth-Jones J, Damstra RJ, Golsch S et al. Twice weekly fluticas-one propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. Br Med J 2003; 326: 1367-70.

8. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 2000; 142: 931-6.

9. Thomas KS, Armstrong S, Avery A et al. Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema. BMJ 2002; 321: 1-7.

10. Bleehen SS, Chu AC, Hamann I et al. Fluticasone propionate 0.05% cream in the treatment of atopic eczema: a multicentre study comparing once-daily treatment and once-daily vehicle cream application versus twice-daily treatment. Br J Dermatol 1995; 133: 592-7.

11. Lucky AW, Leach AD, Laskarzewski P, Wenck H. Use of an emollient as a steroid-sparing agent in the treatment of mild to moderate atopic dermatitis in children. Ped Dermatol 1997; 14: 321^.

12. Turpeinen M. Absorption of hydrocortisone from the skin reservoir in atopic dermatitis. Br J Dermatol 1991; 124: 358-60.

13. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000; 4(37): 1-191. (www.ncchta.org)

14. Long CC, Finlay AU. The fingertip unit - a new practical measure. Clin Exp Dermatol 1991; 16: 444-7.

15. Long CC, Mills CM, Finlay AY. A practical guide to topical therapy in children. Br J Dermatol 1998; 138: 293-6.

16. Devillers AC, Oranje AP. Efficacy and safety of 'wet-wrap' dressings as an intervention treatment in children with severe and/or refractory atopic dermatitis: a critical review of the literature. Br J Dermatol 2006; 154: 579-85.

17. Ramsay, CA, Savoie JM, Gilbert M et al. The treatment of atopic dermatitis with topical fusidic acid and hydrocortisone acetate. J Eur Acad Dermatol Venereol 1996; 7(Suppl 1): 15-22.

18. Ainley-Walker PF, Patel L, David TJ. Side to side comparison of topical treatment in atopic dermatitis. Arch Dis Child 1998; 79: 149-52.

19. Stalder JF, Fleury M, Sourisse M et al. Comparative effects of two topical antiseptics (chlorhexidine vs KMnO4) on bacterial skin flora in atopic dermatitis. Acta Derm Venereol (Stockh) 1992; 176(Suppl): 132-4.

20. Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and Staphyloccus aureus in atopic dermatitis. J Am Acad Dermatol 1992; 27: 29-34.

21. Breneman DL, Hanifin JM, Berge CA, Keswick BH, Neumann PB. The effect of antibacterial soap with 1.5% triclocarban on Staphylococcus aureus in patients with atopic dermatitis. Cutis 2000;66: 296-300.

22. Broberg A, Faergemann J. Topical antimycotic treatment of atopic dermatitis in the head/neck area. A double-blind randomised study. Acta Derm Venereol 1995; 75: 46-9.

23. Ewing CI, Ashcroft C, Gibbs AC et al. Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 1998; 138: 1022-9.

24. Ravenscroft JC, Layton AM, Eady EA et al. Short-term effects of topical fusidic acid or mupirocin on the prevalence of fusidic acid resistant (FusR) Staphylococcus aureus in atopic eczema. Br J Dermatol 2003; 1010-7.

25. Faergemann J, Christensen O, Sjövall P et al. An open study of efficacy and safety of long-term treatment with mometasone furoate fatty cream in the treatment of adult patients with atopic dermatitis. J Eur Acad Dermatol Venereol 2000; 14: 393-6.

26. van der Meer JB, Glazenburg EJ, Mulder PG, Eggink HF, Coenraads PJ. The management of moderate to severe atopic dermatitis in adults with atopical fluticasone propionate. Br J Dermatol 1999; 140: 1114-21.

27. Haaspasaari K-M, Risteli J, Oikarinen A. Recovery of human skin collagen synthesis after short-term topical corticosteroid treatment and comparison between young and old subjects. Br J Dermatol 1996; 135: 65-9.

28. Patel L, Clayton PE, Addison GM, Prince DA, David TJ. Adrenal function following topical steroid treatment in children with atopic dermatitis. Br J Dermatol 1995; 132: 950-5.

29. Jorizzo J, Levy M, Lucky A et al. Multicenter trial for long-term safety and efficacy comparison of 0.05% desonide and 1% hydrocortisone ointments in the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 1995; 33: 74-7.

30. Friedlander SF, Bebert AA, Allen DB. Safety of fluticasone propi-onate cream 0.05% for the treatment of severe and extensive atopic dermatitis in children as young as 3 months. J Am Acad Dermatol 2002; 46: 387-93.

31. Heuck C, Wolthers OD. Calculation of knemometric growth rates in group studies of children treated with exogenous gluco-corticoids. Ann Human Biol 1997; 24: 411-18.

32. Kieffer M, Weismann K, Hjorth N. Pregnancy and treatment with glucocorticoids. Ugeskr Laeger 1986; 148: 160-2.

33. Reitamo S. Lauerma AI. Forstrom L. Detection of contact hyper-sensitivity to topical corticosteroids with hydrocortisone-17-butyrate. Contact Dermatitis 1989; 21: 159-65.

34. Vestergaard L, Andersen KE. Contact allergy to local steroids. Contact allergy to corticosteroids among consecutively tested patients with eczema. Ugeskr Laeger 1997; 159: 5662-6.

35. Aylett SE, Atherton DJ, Preece MA. The treatment of difficult atopic dermatitis in childhood with oral beclomethasone dipropi-onate. Acta Derm Venereol (Stockh) 1992; 176(Suppl): 123-5.

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