Alitretinoin in severe chronic hand eczema

Department of Dermatology,

Queen’s Medical Centre,

Nottingham University Hospitals,

Nottingham, UK

Email: [email protected]

Chronic hand eczema (CHE) is a very common inflammatory skin condition and which has a prevalence of  1–5 % among the adult population.(1,2) It has a major impact and burden on a patient’s quality of life, impeding on day-to-day activities, self-esteem and mood.(3,4) Being localised to a visible part of the body, CHE can cause psychological issues such as anxiety, low mood and phobias.(4) It has also shown to be a cause in loss of earnings, with symptoms such as thick scaly skin, redness, swelling, blisters and painful cracks making certain occupations impossible.

Hand eczema usually follows an intermittent course, developing into a chronic condition, with the disease remaining active even after avoidance of allergens and irritants, occasionally flaring without identifiable triggers.(5) Traditional therapeutic options are limiting and are ofter unable to control the disease. Many patients (2–4%) have disease that is unresponsive to potent topical steroids,(6) which leads to a major management dilemma.

Recent studies have suggested a favourable use of the systemic retinoid alitretinoin (Toctino®) in the treatment of severe CHE unresponsive to potent topical steroids. It is successful in dramatically clearing chronic disease and achieving remission with typical short-term retinoid side-effects.(7) Alitretinoin is available in the UK and Europe and is licensed for use in CHE unresponsive to potent topical steroids. It was approved by the National Institute for Health and Clinical Excellence (NICE) in 2009.(1)

CHE is the result of exposure to irritants or allergens. The clinical characteristics of CHE are well established; however, the pathophysiological mechanisms are not understood fully. Induction of allergic responses activates the epidermal compartment and the immune system by inducing antigen-specific effector and memory T-cells and causing chemokine receptor-regulated leukocyte migration to sites of inflammation.(7,8)

In contact irritancy, skin structured cells as well as immune cells are activated and pro-inflammatory cytokines, such as tumour necrosis factor-α and members of the interleukin-1 family, are induced, in turn further mediating the recruitment of immune cells to produce a reaction.(7,8)

Alitretinoin is thought to disrupt different stages of the inflammatory process seen in chronic contact eczema.(7,8) Recent data have shown that, within structured cells, alitretinoin markedly suppresses the expression of chemokines thought to be relevant (CXCL9 and CXCL10), thus affecting the employment of inflammatory leukocytes and, in turn, might interfere with initiation as well as maintenance of eczema lesions. Alitretinoin suppresses leukocyte activation in a dose-dependent manner.

Overall, alitretinoin could exert an anti-inflammatory effect by interfering with cytokine-induced chemokine production in structural cells in the skin and interfering with recruitment of pathogenic leukocyte subsets to the skin. Furthermore, it modulates leukocyte activation processes to interfere with co-stimulatory molecule function which, in turn, reduces effective antigen presentation to impair leukocyte activation, proliferation and expansion.(8)

Alitretinoin is a retinoid and demonstrates delayed absorption. This is a class effect with retinoids because they are highly lipophilic. This class of drugs also has a high inter- and intra-individual variability of exposure. Variability in exposure does not reduce when the dose is altered for body weight. Administration of alitretinoin with food enhances exposure by a factor of four and variability can be decreased.(9) For this reason, alitretinoin should always be taken with a meal.

Studies undertaken in patients with moderate-to-severe CHE and in healthy volunteers showed no time effect of exposure after chronic administration for up to 24 weeks. A mass balance study showed that oral alitretinoin is absorbed and fully metabolised, with no unaltered drug excreted in the faeces or urine.(10)

The half-life is between two and ten hours in both healthy individuals and those with CHE. The plasma protein binding of alitretinoin is very high, at 99% irrespective of gender. The distribution of the drug is mainly in the plasma. Alitretinoin and its metabolite, 4-oxo-alitretinoin (dose-dependent), can be present in semen but in low levels (8-17ng/ml), having a minimal effect on plasma levels of female partners even if completely absorbed. Thus, barrier contraception for male CHE patients taking alitretinoin is not necessary.

Elimination of oral alitretinoin occurs 11 days post-administration10 and is via urine (63%) and faeces (30%). Mean total excretion is 93.5% of the initial dose given. Excretions comprise the glucuronide of 4-oxo-alitretinoin and numerous small molecule entities that are indistinguishable.

Patients aged over 18 years with CHE resistant to potent topical steroids should receive a dose of 30mg once daily. If this is not tolerated, a reduction to 10mg once daily should be employed. Patients with diabetes, a history of hyperlipidaemia, or risk factors for cardiovascular disease, should initially take 10mg once daily and this can be increased to a maximum of 30mg daily if necessary. The duration of treatment is 12–24 weeks. If there is no response after 12 weeks, alitretinoin should be discontinued. Courses can be repeated in those who relapse.(11)

As in the case of other retinoids, serum cholesterol and trigylcerides should be monitored. The interval of tests can be adapted to the response on the levels of cholesterol and triglycerides seen with use of alitretinoin.

Pregnancy prevention measures must be taken one month before treatment, during treatment, and for one month after treatment.

A study carried out by Bollag et al in 1999 showed a ‘very good’ or ‘good’ outcome response for their CHE in 89% of patients. A total of 38 patients were included in this study.12 The phase II trial was a dose-ranging, double-blinded, randomised, placebo-controlled study in 312 patients with moderate-to-severe CHE. Alitretinoin improved disease status significantly in a dose-dependent trend graded by a Physician Global Assessment (PGA) rating of ‘clear’ or ‘almost clear’ in up to 54% of patients.

The BACH (Benefit of Alitretinoin in Chronic Hand eczema) phase III trial, and the largest conducted in CHE, was carried out in 2008.(13) BACH was a prospective, randomised, double-blind, placebo-controlled, parallel-group study in 1032 patients. Patients were randomised to receive either: placebo; 30mg alitretinoin; or 10mg alitretinoin daily for up to 24 weeks. The PGA was the primary outcome measure recorded at baseline and then four-weekly, with a response defined as a PGA rating of ‘clear’ or ‘almost clear’ hands. A second parameter measured was the modified Total Lesion Symptom Score (mTLSS) measuring scores for erythema, vesiculation, hyperkeratosis, pruritis, pain, oedema, fissures and desquamation. Both doses of alitretinoin showed significantly greater efficacy compared with placebo at the end of the treatment course. After 24 weeks the median reduction in mTLSS in the 30mg and 10mg groups was 75% and 56% respectively, compared with 39% for placebo. The mTLSS was reduced by 58% in the 30mg alitretinoin group after 12 weeks.

Alitretinoin is generally well tolerated in the treatment of patients with CHE. There are no safety issues noted in special safety assessments conducted during clinical studies to detect effects shared with other retinoids. There were no effects on the incidence or severity of psychiatric adverse events or bone mineralisation. Ophthalmological assessments noted the occurrence of dry eyes but there were no effects on retinal function.

Adverse events reported from the trials were usually dose-dependent and consistent with those found in the retinoid group. Headache was the most common adverse event in patients treated with 30mg alitretinoin, and usually occurring within the first ten days. Headaches were treated with simple analgesics and occasional dose reduction.

Mucocutaneous reactions were seen in 10% of those participants of the BACH study taking 30mg alitretinoin. This is thought to be lower than those reported for other retinoids. Other adverse events noted were: nasopharyngitis, upper respiratory tract infection, erythema, eczema, pruritus, dry lips, nausea, dry mouth, and flushing.

Laboratory abnormalities seen in the BACH study were those typically seen for the retinoid class of drug. Increases in serum cholesterol and triglyceride levels were most common. These changes normalised or improved within a four-week period after stopping the medication. Reduced thyroid-stimulating hormone levels were reported in the 30mg alitretinoin group. This was not always linked with a reduction in T4 and no clinical hypothyroidism was evident, nor needed intervention.

There seemed to be little or no effect on liver enzymes, bilirubin levels or blood creatine phosphokinase levels.(13)

Serum abnormalities in retreatment studies were similar to those seen in the BACH trial.(14)

Blood donation should be avoided during treatment and for at least one month after stopping treatment. Serum lipids should be monitored (more frequently in those with diabetes, history of hyperlipidaemia, or risk factors for cardiovascular disease). Alitretinoin should be discontinued if uncontrolled hyperlipidaemia occurs. Other cautions are a history of depression or a dry eye syndrome.(11)

In women of childbearing age and potential, pregnancy should be excluded one month before treatment, again up to three days before treatment, every month during treatment and five weeks after stopping treatment with alitretinoin. Women must practice effective contraception for at least one month before starting treatment, during treatment, and for at least one month after stopping treatment. Women should be advised to use at least one method of contraception but ideally they should use two methods. The oral progestogen-only contraceptives are not considered effective in this case. Barrier methods should not be used alone but can, and should, be used in conjunction with other contraceptive methods. Women should be advised to immediately discontinue treatment and to seek prompt medical attention if they become pregnant during treatment or within one month of stopping treatment.(11)

Uncontrolled hyperlipidaemia, uncontrolled hypothyroidism, hypervitaminosis A, hepatic impairment, renal impairment, pregnancy and breast feeding are all contraindications when considering use of alitretinoin.

A raised serum concentration of triglycerides and cholesterol can lead to increased risk of pancreatitis, especially if the triglyceride level is >9mmol/l. Flushing, headache, changes in thyroid function tests, anaemia, myalgia, raised creatine kinase, arthralgia, conjunctivitis, dry eyes (sometimes decreased tolerance to contact lenses), eye irritation, dryness of skin and lips, cheilitis, erythema and alopecia are all potential side-effects of alitretinoin use. Less commonly, epistaxis, hyperostosis, ankylosing spondylitis, blurred vision, cataracts, pruritus and asteototic eczema are seen. Benign intracranial hypertension (discontinue if severe headache, nausea, vomiting, papilloedema, or visual disturbances occur) and vasculitis, keratitis and impaired night vision have been reported very rarely.(11)

Ketoconazole can increase the plasma level of alitretinoin if taken together. Simvastatin concentration can be reduced by alitretinoin making it less effective. Tetracyclines, when taken with retinoids, have a possible increased risk of benign intracranial hypertension. Vitamin A given with retinoids can lead to hypervitaminosis A.(11)

There are limited treatment options available to patients with CHE resistant to topical steroids, thus treatment guidelines are now including alitretinoin. NICE in the UK has recommended alitretinoin use in those patients with CHE who fail to respond to topical steroid treatment.(1)

Guidelines from Germany on treating CHE recommend alitretinoin use for persistent or chronic relapsing hand eczema where topical steroids and UV therapy have failed.(15) An Italian advisory publication suggested the use alitretinoin for severe disease and forms of CHE that fail to respond to topical therapy or phototherapy.(16)

Because CHE can be resistant and difficult to treat, and some cases can have an inadequate response to potent topical steroids, alitretinoin provides a successful management strategy. However, there is no doubt that alitretinoin use incurs costs from both the cost of the medication and from the monitoring required. Blood tests, clinic appointments and patient’s time spent attending all incur costs. Alitretinoin costs £411.43 for a pack of 30×30-mg capsules. Costs may vary in different settings because of negotiated procurement discounts.(11)

There are no trials comparing the efficacy of alitretinoin to comparators (azathioprine, ciclosprorin, PUVA); therefore, alitretinoin can only be compared with supportive care. It was noted that, after analysis and modifications, 30mg alitretinoin compared with best supportive care gave an incremental cost-effectiveness ratio estimate of approximately £131,000 per quality-adjusted life year gained.11 The benefit of alitretinoin had been established in a population with severe CHE for whom the manufacturer had calculated a Disease Life Quality Index (DLQI) of 15 and its economic case has been made for this type of patient. Treatment with alitretinoin for people whose eczema is sufficiently severe to result in a DLQI score of 15 or more would represent a cost-effective use of NHS resources in the UK.

Alitretinoin (Toctino®) is a licensed treatment for chronic hand eczema unresponsive to potent topical steroids throughout Europe and the UK. It offers a well-tolerated, evidence-based, alternative therapeutic option for a high impacting, persistent condition.

• Alitretinoin (Toctino®; Basilea) is licensed for use in adults with severe chronic hand eczema that is unresponsive to potent topical steroids.
• Alitretinoin is a derivative of retinoic acid (9-cis-retinoic acid) that produces anti-inflammatory effects by suppressing specific chemokines.
• Studies have shown alitretinoin to safely clear chronic hand eczema with minimal adverse effects in 50% of patients treated by 24 weeks.
• Alitretinoin is well tolerated; common side-effects are those typically seen with other retinoids.
• Alitretinoin is the first and only evidence-based therapy specifically licensed for chronic hand eczema.

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