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Jørgen Serup DMSc
Department of Dermatology
Bispebjerg University Hospital
Long-term (chronic) severe cases of hand eczema can be very difficult to treat successfully. A range of immunosuppressants, including ciclosporin, azathioprine and methotrexate, have been used off-label for severe eczema, even though there is a relative lack of evidence of effectiveness. This empirical treatment approach for severe cases varies between countries and between clinics and there is diversity of expert opinion on treatment. No dose-titration studies on immunosuppressants in hand eczema have been conducted and there are no experimental data to support a standard dose. Alitretinoin (Toctino; Basilea Pharmaceuticals) is the only licensed oral treatment for severe chronic hand eczema and offers a therapeutic opportunity for a potentially debilitating condition. There is no rationale for head-to-head comparisons with immunosuppressants and the pre-licensing studies were, consequently, placebo-controlled.
There is no generally accepted standard for classification of hand eczema. Both endogenous and exogenous factors play a role in the development of the disease. Contact with irritants and allergens, genetic predisposition and background factors, such as atopy, are involved. A number of different mechanisms and triggers are involved, including local factors in the affected skin (hyperkeratosis), individual response patterns, skin barrier deficiencies, local inflammation, and the nonspecific or specific interaction with the immune system, which is of key importance in allergic eczema and the rationale behind trying immunosuppressants in selected eczema patients with proven allergic sensitisation of clinical relevance, if contraindications are not present. As mentioned, such treatment is not evidence-based and off-label.
Prevalence of hand eczema
Hand eczema is regularly encountered in clinical practice. It is usually long-lasting, with a mean duration of 11.6 years from the time of first appearance to the time of clinical status. The prevalence for hand eczema in the general population is estimated to be 1–5%. The yearly incidence of hand eczema is approximately 7–12% in the general population in Northern Europe and possibly higher in the USA; however, only a third or less of this population actually seeks medical consultation and treatment. Sparse data are available but the proportion of patients with severe chronic hand eczema is estimated to be 5–7% of all patients with hand eczema, and 2–4% are considered to be refractory to potent topical corticosteroids, potentially representing up to 0.14–0.48% of the total population of patients with hand eczema, in countries where the disease is most prevalent. The number of patients who are candidates for alitretinoin treatment is small, but practically very important.
Clinical efficacy and safety
Systemic retinoids, such as acitretin registered for the treatment of psoriasis, have now and then been prescribed for hand eczema, albeit their use in this indication is not evidence-based. Alitretinoin (9-cis-retinoic acid) is a retinoid that is capable of activating all retinoic acid (RAR) receptors as well as retinoid X receptors (RXR), thereby having the potential to exert effects on epidermal proliferation and maturation and also on inflammation. Toctino is currently approved in Europe as a new once-daily treatment for adults with severe chronic hand eczema unresponsive to potent topical corticosteroids. Standard treatment is 30mg once daily for 12–24 weeks as an initial treatment course; 10mg capsules are available. Alitretinoin is eliminated in one to three days, in contrast to acitretin, which is eliminated over a period of months. Acitretin is contraindicated in women of childbearing potential for two years following cessation of treatment and its use on an empirical basis in women of childbearing potential is ethically controversial and not recommended. Alitretinoin is contraindicated in women of childbearing potential unless strict pregnancy testing and contraception is followed before, during and one month after cessation of treatment.
In a randomised, double-blind, placebo-controlled trial, Ruzicka et al (2008) studied the efficacy and safety of oral alitretinoin (10mg and 30mg) in 1032 patients with severe hand eczema refractory to local corticosteroids in 111 centres in Europe and Canada. All types of hand eczema were included in the study. ‘Clear’ and ‘almost clear’ hands were observed in up to 48% of patients in the alitretinoin group vs 17% in the placebo group. Alitretinoin was generally well tolerated. Side-effects were dose-dependent and included headache, mucocutaneous events, hyperlipidaemia and decreased thyroid parameters. Median time to relapse after a 24-week treatment course was approximately six months. The results of this study were confirmed in an open-label trial of 249 patients with hand eczema. Successful retreatment with alitretinoin in patients with relapsed hand eczema and ‘clear’ or ‘almost clear’ hands following a previous aliretinoin treatment was studied in 117 patients. Response rates were up to 80% in patients treated with 30mg daily vs 8% for the placebo group; response rates were 48% vs 10% for patients treated with 10mg and placebo respectively.
Impact on quality of life
The personal and social burden of chronic hand eczema is high. Its highly visible nature and the social stigma associated with it can be burdensome and can have a negative impact on the patient’s quality of life (QoL). Severe chronic eczema is associated with persisting and disfiguring changes in the appearance of the hands. Chronic hand eczema can result in substantial occupational, personal, social, and psychological disability including periods of prolonged sick leave and unemployment, anxiety, low self-esteem and social phobia. Hand eczema can also reduce quality of life of patients by causing sexual dysfunction that is exacerbated by concomitant depression owing to the condition.
The QoL for patients with dermatological diseases has become an important outcome variable in the last 10 years. The most frequently used questionnaires in dermatological research are self-reported and dermatology specific, such as the Dermatology Life Quality Index (DLQI), Dermatology-Specific Quality of Life (DSQL) and Skindex-29.
In hand eczema, severity of disease correlates closely with DLQI score. A post-hoc analysis of phase II data indicated that improvements in severity of chronic hand eczema are associated with significant improvements in DLQI score.
Work-related cost of illness
In Germany, 26% of reported and 36% (~8460 cases) of all confirmed work-related diseases are skin-related, and in >90% of these cases it is the hands that are affected. In 2008, Diepgen and Hieke retrospectively assessed the costs of occupational skin diseases (specifically hand eczema) for 151 German patients from medical records over a period of 12 months. The German Statutory Accident Insurance (DGUV) was the payer for all the patients and costs were calculated from a societal perspective. The resources utilised by these patients most frequently were visits to the dermatologist, application of topical steroids, and taking sick leave. A total of 55% of patients in the moderate severity group and 68% of patients in the high severity group reported at least one day lost from work as a result of their condition. Direct costs included out-patient rehabilitation, in-patient rehabilitation, diagnostic services, complementary therapies, medication costs and estimated patients’ out-of-pocket costs. Indirect costs, that is, costs associated with days lost from work, accounted for more than 70% of the total and were the dominant cost-related factor for patients with chronic hand eczema. The second most important cost-driver was in-patient rehabilitation, which accounted for approximately 13% of total costs and 42% of direct costs. The direct and indirect costs per patient for this population are shown in Table 1.
Based on this analysis, the authors concluded that the total annual costs of occupational contact dermatitis are similar to the costs of severe psoriasis and atopic dermatitis. Total annual costs of new cases covered by the DGUV with confirmed occupational aetiology are estimated to amount to €60 million.
A treatment course for Toctino is for up to 24 weeks depending on response. Treatment should be discontinued once the disease has cleared and discontinuation should be considered for patients who still have severe disease after the initial 12 weeks of treatment. In the event of relapse, patients might benefit from further treatment courses. From the pivotal phase III study by Ruzicka et al, time to remission was determined as short and the time to relapse as long. Based on the phase III trial data, economic models have been prepared and the cost-effectiveness determined.
Blank and colleagues (2010) looked at cost-effectiveness from a Swiss perspective. A Markov model was used to estimate direct medical costs and clinical effectiveness (quality adjusted life years; QALYs) of treating severe chronic hand eczema patients with alitretinoin. The model was developed to simulate the transitions of a hypothetical cohort of patients with severe, chronic hand eczema, refractory to topical steroids, from the time of receiving Toctino or supportive care plus optimised emollient therapy, until all patients in both arms were receiving alternative care, having eventually failed on either therapy. The structure followed the patients over a number of model iterations, for approximately 22 years, allowing for changes in health status at the end of each treatment cycle. The model estimated an incremental cost-effectiveness ratio (ICER) of €14,816 per QALY. This ICER is well below existing cost-effectiveness thresholds and the treatment is considered cost-effective in Switzerland.
A similar analysis has been presented for the UK. The National Institute for Health and Clinical Excellence (NICE) estimated in a budget impact analysis that Toctino would mainly replace phototherapy. In this case, Toctino would even be cost-saving and it was included in a cost-saving guidance by NICE.
Chronic hand eczema is a significant burden for the patient, both medically and socially, and can impact greatly on quality of life and ability to work. Older immunosuppressant treatments, such as ciclosporin and azathioprine, were often used off-label, on an empirical basis and without clinical evidence to support their use, leaving many patients in a chronic disease state. Toctino is a new oral treatment for adults with severe chronic hand eczema that is refractory to potent topical corticosteroids. Its efficacy, acceptable safety profile and recognised cost-effectiveness in pharmacoeconomic models makes it a significant medical achievement in the field of contact dermatitis and occupational skin disease.
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