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Published on 2 November 2009

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Severe Hand Eczema-the role of Alitretinoin (Toctino)

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Severe hand eczema has a detrimental effect on the patient’s work and family life and may require referral to dermatologist

Robin Graham-Brown

A significant number of patients, their families, friends and employers find hand eczema a huge burden[1] and are often deeply disappointed with the relatively poor control that is achievable with current therapeutic options. People with severe eczema or eczema resistant to treatment may require referral to a dermatologist.

Hand eczema is very common,[2] with up to 10% of the population suffering at some point in their lives. It may occur just on the hands or also on the feet, or be part of a more generalised eczema. A number of factors may contribute to the cause, such as genetic susceptibility; exposure to irritants at home or at work and contact allergic dermatitis.[3] A past history of atopic eczema is a particularly strong risk factor.[4] Precisely defining the cause can be extremely difficult.

A genetically predisposed individual exposed to regular contact with water, soaps, detergents, solvents and other irritant materials in the workplace or the home is very likely to develop problems with their hands. Once the problem has begun it often becomes chronic and fails to settle adequately without treatment, even when the patient is completely and permanently removed from the damaging environment.

About 50% of patients with hand eczema seek dermatological advice; 507% have really severe, incapacitating disease, with up to 15% having time away from work, and 2-4% are refractory to topical therapy.[2]

Initial therapeutic options
The first step in managing hand eczema is to discuss constitutional predisposition, irritant exposure and contact allergy. Wise counsel for someone with a strong atopic history, especially with ongoing eczema, is to avoid occupations that will expose the skin to excessive washing or chemical exposure in the first place. Changing an established career path can be difficult but attempts to reduce irritant contact with the skin are essential. Equally important is the use of emollients. Many agents are available, with much variation across Europe, and there are no hard and fast rules. However, the use of non-soap cleansers and the liberal application of moisturisers to the skin will help many to cope with daily life. Excluding contact allergy requires referral to a dermatologist for patch testing.

Suppressing inflammation
The other major challenge is to suppress inflammation, which may be more or less constant, but is often intermittent. Topical corticosteroids (TCS) are undoubtedly the mainstay of the active management of patients with any inflammatory skin disease, and chronic hand eczema is no exception. By and large, potent agents are required and this immediately presents an issue. Although the use of TCS may result in adequate control, in some patients with particularly severe disease this requires the use of strengths and quantities that are essentially unsafe over prolonged periods- the main risk being skin thinning (atrophy).

In order to get around this, dermatologists may resort to the use of a range of unlicensed therapies. For example, a topical calcineurin inhibitor, such as Tacrolimus 0.1% ointment may be prescribed to be used alone, or in concert with TCS. Patients attending dermatology units may be offered topical PUVA (psoralen+ UVA). This is time consuming but can be helpful in
selected patients.

If topical therapy, with or without PUVA, fails to relieve the symptoms and provide control, systemic treatment will be needed, namely:

  • Systemic steroids.
  • Azathioprine.
  • Methotrexate.
  • Ciclosporin.

Each of these has its advocates and they are used in different ways by different clinicians for different patients; all are unlicensed for this indication; all have their pros and cons.

Management of pompholyx

Pompholyx refers to a troublesome clinical condition in which vesicles and bullae develop. Patients develop bouts of intense irritation associated with acute blister formation on the palms (and soles if the feet are affected) and the sides of the digits. The blisters mature over the course of a few days and may become purulent. Eventually they dry up, often leaving scaly, fissured areas in their wake. Soon another wave follows. This form of hand eczema is traditionally treated with potassium permanganate soaks (a very messybusiness), TCS and antibiotics. Systemic therapy is often required for severe disease because, quite simply, nothing else works.

Alitretinoin
Retinoids (retinoic acid, adapalene, acitretin, and before it etretinate, and isotretinoin) are well known to dermatologists and have been used extensively for the management of psoriasis, other hyperkeratinising disorders and acne for many years. It was something of a surprise when a large controlled trial appeared in 2008 suggesting that another drug in this class might be useful in chronic hand eczema.[5] That drug was alitretinoin (9 cisretinoic acid), a naturally occurring retinoid with both retinoid receptors (RAR and RXR). The BACH Study, together with previous uncontrolled observations and a dose-ranging trial published in 2004,6,7 constitute the body of evidence that supports the use of alitretinoin in chronic hand eczema.

The BACH Study was large: there were over 300 patients in each active arm and 155 in the placebo arm. It showed that a single daily dose of either 10 mg or 30 mg of alitretinoin produced a significantly better outcome than placebo. The 30 mg group performed better than the 10 mg in terms of proportions of patients achieving complete or almost complete clearance, but there were significant improvements, for those patients that responded, in both groups. All forms of hand eczema appeared to respond. Although fissuring and hyperkeratosis were the predominant features in the majority of patients, a good number had vesicular disease (ipompholyx) and they did well too. The responses were sustained in many patients and, importantly, the effect seemed to be repeatable. If patients relapsed most did well with a reintroduction of the drug at the same dose.

Side-effects
Alitretinoin is highly teratogenic-as are all the other retinoids-and careful counselling of female patients of child-bearing years is absolutely mandatory.

A few niggly side-effects came to light in the study, such as a dose-related tendency to headaches and the expected rise in lipids in a proportion of patients. Headaches occasionally resulted in patients dropping out of the study. Mucocutaneous side-effects, which are prominent and often troublesome with existing dermatological retinoids, were strikingly insignificant. There were no issues with thyroid function-an important concern, since alitretinoin has both RAR and RXR receptor activity and RXR active compounds (like bexarotene) can affect thyroid function markedly.

There are some unanswered questions that will need to be addressed by experience in clinical practice and by further studies. The design of the study did not allow for dosage titration, so it is not know whether a failure to respond to 10 mg would be overcome by a dose increase, nor whether a response to an initial dose of 30 mg might be maintained with, say, fewer headaches, by a drop to 10 mg.

Appraisal and guidance
The evidence suggests that the drug works in this difficult group of patients and it has, accordingly, been licensed for use. In the UK, it has also been subject to a NICE appraisal and they issued guidance in August 2009 to physicians:[8]

“Alitretinoin is recommended, within its licensed indication, as a treatment option for adults with severe chronic hand eczema that has not responded to potent topical corticosteroids if the person has:

  • Severe disease, as defined the physician’s global assessment
  • A dermatology life quality index (DLQI) score of 15 or more”.

NICE then goes on to say that the drug should be stopped as soon as an adequate response is achieved, or if the eczema remains severe at 12 weeks, or if an adequate response has not been achieved by 24 weeks.

In practice
A new treatment (Alitretinoin) has emerged for a difficult and troublesome dermatological condition. I have now had successful outcomes with nearly a dozen patients in my own practice. It is relatively free of side-effects but headaches may limit its usefulness for a few and it will need to be used with caution in women of childbearing age. Its exact place in the therapeutic armoury will take time to emerge but it is a real advance and offers real hope to a group of patients who have often suffered greatly in the past.

References
1. Cvetkovski RS, et al. Quality of life and depression in a population of occupational hand eczema patients. Contact Dermatitis 2006:54:106-111
2. Diepgen T, et al. Management of chronic hand eczema. Contact Dermatitis 2007:57:203-210
3. Hogan DJ, et al. The prognosis of contact dermatitis. J Am Acad Dermatol 1990:23:300-307
4. Dickel H, et al. Impact of atopic skin diathesis on occupational skin disease incidence in a working population. J Invest Dermatol 2003:121:37-40
5.
Ruzicka T, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008:158:808-817
6. Bollag W, et al. Successful treatment of chronic hand eczema with oral 9-cis-retinoic acid. Dermatology 1999:199:308-312
7. Ruzicka T, et al. Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, doubleblind, placebo-controlled, multicenter trial. Arch Dermatol 2004:140:1453-1459
8. Alitretinoin for the treatment of severe chronic hand eczema. National Institute for Health and Clinical Excellence.



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