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Sakari Reitamo
MD PhD
Specialist in Dermatology and Venereology
Department of Dermatology Hospital for Skin and Allergic Diseases
Helsinki
Finland
E:[email protected]
Atopic dermatitis (AD) is a clinical symptom, which is influenced by both genetic and environmental factors. The disease is characterised by itchy dry skin, a chronically relapsing course and a tendency for cutaneous infections. In a number of patients AD progresses to widespread and severe disease which is difficult to treat. The severity grading of AD is dependent on both subjective and objective factors. In clinical studies the inclusion of patients is often based on the grading of Rajka and Langeland, which takes into account disease extent, duration over a year and subjective symptoms such as itch and/or loss of sleep.(1)
The therapies used to treat atopic dermatitis include topical corticosteroids as firstline therapy, with systemic corticosteroids, natural or artificial ultraviolet (UV) therapies, and immunosuppressive agents such as azathioprine, methotrexate and ciclosporin as secondline therapies. Most of the published studies on topical corticosteroids are of only short-term duration and often compare one corticosteroid with another. There are only a few published controlled studies looking at long-term treatment in AD. Such studies have usually compared combination therapy of corticosteroids with either immunosuppressants or UV treatment. More recently, open studies have examined the tolerability of tacrolimus ointment and its efficacy compared with placebo and steroid therapy. Tacrolimus ointment is currently the only alternative to corticosteroids as monotherapy of severe atopic dermatitis.
Treatment of severe AD
Corticosteroids
Corticosteroids are potent anti-inflammatory agents. Their effect is mediated by several mechanisms leading to inhibition of phospholipase A2 and hence formation of proinflammatory prostanoids, inhibition of cytokine production, reduction in the number of antigen-presenting cells, and vasoconstriction. In humans, corticosteroids have an effect on practically all cells, so their side-effects are not limited to the skin.
Systemic corticosteroids
In severe AD, systemic corticosteroids are usually used on a short-term basis. Although clearly effective, there are no published short-term or long-term studies available to support their use. Therefore they should be used with caution and mainly as emergency short-term therapy of severe AD.
Topical corticosteroids
AD treatment is usually based on topical corticosteroids, which until recently were the only topical treatments whose efficacy had been demonstrated in randomised controlled studies. Although topical corticosteroids are often used long term for the treatment of atopic dermatitis, they are licensed only for short-term use. There are very few data available on whether they should be used until all symptoms of the disease have vanished, or sparingly in order to have the best efficacy while avoiding side-effects. A recent study by Berth-Jones et al suggested that fluticasone cream or ointment twice weekly could be an effective maintenance treatment for patients with serious atopic dermatitis.(2)
A major problem of both systemic and topical corticosteroids is their inhibitory effect on collagen synthesis, which results in reduced skin thickness and also telangiectasiae. Other adverse events associated with corticosteroids include hirsutism and contact allergy.
UV treatment
Most patients with AD improve with exposure to natural sunlight during the summer months, although the disease can be exacerbated, especially in the more severe forms of AD. Systemic UV radiation therapy has been used since 1948; however, due to practical problems it has proved difficult to study in a blinded, controlled manner, and only a few studies are available. UV is a major cause of skin cancer, which limits its use as therapy of severe atopic dermatitis. Usually it is used in combination with topical corticosteroids.
Immunosuppressants
In addition to systemic corticosteroids, the other systemic immunosuppressive agents used in AD include azathioprine, methotrexate and ciclosporin. Oral methotrexate has not been evaluated in controlled studies. The first controlled study on azathioprine appeared recently – the clinical efficacy was not remarkable.(3) In contrast, oral ciclosporin has proved very effective both in short-term and long-term intermittent treatment of severe atopic dermatitis in adults(4,5) and in children.(6) Its efficacy is clearly superior to that of UV therapy. Oral pimecrolimus has a similar mode of action to that of ciclosporin and tacrolimus. It is currently under investigation in clinical studies in patients with severe AD.(7) Compared with ciclosporin, it may have a better benefit/risk ratio.
Topical immunomodulators
Tacrolimus (Protopic 0.1 and 0.03%; Fujisawa) and pimecrolimus (Elidel 1%; Novartis) are the two topical immunomodulators currently marketed for atopic dermatitis. Several placebo-controlled studies with tacrolimus and pimecrolimus have shown their efficacy as compared with vehicle treatment. In tacrolimus studies, 40–50% of the patients have had severe AD. Of these compounds, tacrolimus ointment has demonstrated efficacy in both moderate and severe AD, whereas pimecrolimus showed efficacy in patients with mild-to-moderate atopic dermatitis. (8)
Tacrolimus vs corticosteroids
Short-term studies of three weeks’ duration compared tacrolimus with hydrocortisone acetate in children(9) and with hydrocortisone butyrate in adults.(10) These studies showed that tacrolimus at the lower concentration of 0.03% once daily is superior to 1% hydrocortisone acetate twice daily. In children with moderate AD, tacrolimus 0.03% once or twice daily showed similar efficacies, whereas in severe AD the twice-daily regimen was clearly superior to once-daily treatment.(11)
Hydrocortisone butyrate is a moderately potent to potent corticosteroid. Tacrolimus at 0.1% had a similar efficacy as hydrocortisone butyrate, whereas 0.03% tacrolimus was clearly inferior in efficacy.
Long-term safety studies have suggested that tacrolimus ointment has good efficacy in the treatment of severe AD.(12) So far there is only one long-term study comparing tacrolimus ointment and corticosteroids. This study was of six months’ duration and is available as a congress abstract.(13) In this study, tacrolimus 0.1% treatment for six months was superior to conventional corticosteroid treatment.
Adverse events
A burning sensation of the skin was the only adverse event that showed a higher incidence with tacrolimus ointment compared with the vehicle control in short-term studies. In long-term studies, burning skin, erythema and pruritus were common but tended to occur only during the first few days of treatment. Burning and also erythema of the face were aggravated by alcohol uptake in some patients. The cause of burning is not known. Uncontrolled safety studies of one year’s duration did not show any safety concerns.(12) Bacterial colonisation with Staphylococcus aureus was reduced to a great extent and there were no other apparent signs of immune suppression.(14) In historical comparisons there was no apparent increase in herpes simplex infections; also, there was no decrease in recall antigen reactions. Long-term studies suggest that tacrolimus ointment has a good safety profile and can therefore be used long term. During long-term studies with tacrolimus, some of our patients experienced several months in which no treatment was necessary. It would be of interest to assess this prospectively. Long periods of clearance, in which treatment would be unnecessary, would be a great advantage over conventional corticosteroid treatment.
Laboratory profiles during several long-term studies have been unremarkable. Drug levels have decreased a few days after starting therapy for both tacrolimus and pimecrolimus. During long-term treatment, about 75% of the patients did not show detectable blood levels of tacrolimus.(12) The only exceptions have been children with Netherton’s syndrome, an autosomal recessive disease characterised by congenital erythroderma, who despite a good treatment result showed high tacrolimus trough levels.
Why should patients be treated with tacrolimus monotherapy?
We have experience from many patients who used ciclosporin together with topical corticosteroids, and who have significantly improved after switching to tacrolimus monotherapy. This suggests that tacrolimus monotherapy can greatly improve the treatment of severe AD (Figure 1). When tacrolimus is used as long-term treatment in a clinical research project that emphasises treatment of all eczema until the skin is totally cleared and the itch gone, an improvement in patients with severe atopic dermatitis of at least 80% can be expected in half of the patients.
[[HPE11_fig1_21]]
Total use of tacrolimus ointment decreases over time, and some patients also have treatment-free periods of several weeks. This improvement of the skin after long-term tacrolimus treatment raises questions as to whether all skin symptoms in AD could become secondary. This would mean redefinition of the disease, as itchy dry skin has been the central prerequisite for the diagnosis of AD.
Sugiura et al showed recently that by treating the face only with tacrolimus, and the rest of the body with corticosteroids, there were, after an initial response, quite poor long-term results. These results were dependent on the severity of dermatitis, with treatment results inversely related to severity of dermatitis.(15) We can confirm these findings from several patients treated outside clinical trials.
Conclusion
The main advantage of topical noncorticosteroid immunomodulatory agents such as tacrolimus ointment is that they do not cause skin atrophy(16) and therefore do not prevent healing of the skin. The clinical data collected so far indicate that during long-term use there is no increased risk of skin cancer, infection or other undesirable immunosuppressive effects. Therefore tacrolimus ointment could become a firstline therapy for serious AD.
References
- Hanifin JM, Langeland T. Acta Derm Venereol 1989;Suppl 144:13.
- Berth-Jones J, Damstra RJ, Golsch S, et al. BMJ 2003;326:1367.
- Berth-Jones J, Takwale A, Tan E. Br J Dermatol 2002;147:324.
- Zonneveld IM, de Rie MA, Beljaards RC, et al. Br J Dermatol 1996;Suppl 135:15.
- Sowden J, Berth-Jones J, Ross JS, et al. Lancet 1991;338:137.
- Berth-Jones J, Finlay AY, Zaki I, et al. J Am Acad Dermatol 1996;34:1016.
- Wolff K, Caro I, Flemming C, et al. Treatment with oral pimecrolimus significantly improves atopic eczema with a clear dose-response effect [poster]. Annual meeting of the European Academy of Dermatology and Venereology, Barcelona, 15–19 October 2003.
- Reitamo S, Remitz A, Kyllönen H, Saarikko J. Am J Clin Dermatol 2002;3:381.
- Reitamo S, Van Leent EJM, Ho V et al. J Allergy Clin Immunol 2002;109:539.
- Reitamo S, Rustin M, Ruzicka T, et al. J Allergy Clin Immunol 2002;109:547.
- Reitamo S, Harper J, Bos J. Br J Dermatol In press 2003.
- Reitamo S, Wollenberg A, Schöpf E, et al. Arch Dermatol 2000;136:999-1006.
- Reitamo S, for the European tacrolimus ointment study group. 0.1% tacrolimus ointment is significantly more efficaceous than a steroid regimen in adults with moderate to severe atopic dermatitis [poster]. 12th Congress of the European Academy of Dermatology and Venereology, St Julien’s, Malta, 27 February – 1 March 2003.
- Remitz A, Kyllönen H, Granlund H, Reitamo S. J Allergy Clin Immunol 2001;107:196.
- Sugiura H, Tsukinowa-cho S, Uehara M, et al. Arch Dermatol 2000;136:1062.
- Reitamo S, Rissanen J, Remitz A, et al. J Invest Dermatol 1998;111:396.
