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New and Existing Therapeutic Options for Hand Eczema

L. Robertson, MD, FRCPC
Department of Medicine, University of Calgary, Calgary, AB

ABSTRACT

Hand eczema affects up to 10% of the population and encompasses a diverse range of morphological presentations and underlying pathophysiological processes. This article will review the new and existing treatments that are available for this common dermatologic problem.

Key Words: botulinum toxin; calcineurin inhibitors; corticosteroids; hand eczema; immunomodulators; iontophoresis; phototherapy; retinoids; systemic immunosuppressive therapy

There is not, as yet, a standardized system for the classification of hand eczema. Warshaw et al., however, outlined a comprehensive clinical classification of hand eczema based on an extensive literature review, as well as from personal experience.1 Clinical manifestations of the disorder include erythema, edema, scaling, hyperkeratosis, vessiculation, fissuring, papules, and plaques. Morphological subtypes and patterns of distribution may suggest causation, but these are not reliable predictors and etiology is usually multifactorial.2,3 Atopic skin diathesis is believed to play a role in hand eczema in up to 50% of cases.4 The 2 other most important causative factors are contact allergy and irritant exposure. Additional contributory factors include friction, occupation, low humidity, psychological stress, low socio-economic status, and hyperhidrosis.5,6 A specific etiology cannot be identified in some patients with hand eczema.5

Hand eczema often runs a chronic, relapsing, and remitting course despite appropriate preventative measures and treatment.5,7,8 Several studies have demonstrated the psychosocial burden of chronic hand eczema on patients’ lives, as well as its burden on society.9-11 Despite the enormity of the problem, few well-designed, randomized controlled trials evaluating therapies have been carried out. In all hand eczema trials since 1977,3 only 2,142 patients have been enrolled, and a recent European survey conducted on hand eczema identified only 31 randomized controlled trials involving a total of 1,200 participants.12 The paucity of evidence-based data on therapeutic options for hand eczema has left clinicians with no clear direction for treating those patients who do not respond to conventional therapy.

Management - Preventative Measures

The regular use of hand emollients and avoidance of frequent contact with irritants such as water, soap and detergents are the mainstays of therapy. Rubber gloves can exacerbate hand eczema, which can usually be avoided by wearing cotton liners. Contact allergy is responsible for hand eczema in as many as 47% of cases and all patients should be considered for patch testing to identify relevant allergens.13 A recent study demonstrated the persistence of contact sensitivity in up to 74% of hand eczema patients who were followed for 8 years,14 emphasizing the importance of continued allergen avoidance over time. Common contact allergens that can cause hand dermatitis include nickel, potassium dichromate, rubber chemicals, and biocides.

Topical Treatments

Corticosteroids

Considered as the first-line therapy in the treatment of hand eczema, several trials have evaluated the efficacy of mild, moderate, or potent topical corticosteroids for hand eczema.15-17 However, there are no standard recommendations about how these agents should be used.

Generally, the choice of steroid potency is influenced by factors such as eczema severity, morphology, and the area involved. Drug delivery is enhanced with an ointment vehicle, as well as occlusion. In addition, water soaks for 20 minutes prior to steroid application appears to give superior results.18 Agents such as salicylic acid, tar derivatives, and anthralin are adjunctive therapies and are especially useful for hyperkeratotic eczema.

It is important to keep in mind that topical corticosteroids may also be allergens. Consquently, the possibility of a corticosteroid allergy should always be considered before attributing treatment failure to the disease itself.

Immunomodulators

The effectiveness of topical calcineurin inhibitors in the treatment of atopic dermatitis has been well established; however, their therapeutic role in hand eczema has not been studied in randomized, double-blind, controlled trials.

In a prospective, open, multicenter study of 29 patients with occupational hand eczema, tacrolimus 0.1% (Protopic®, Astellas Pharma) was applied twice daily for 4 weeks, followed by a 2 month optional treatment period, which resulted in complete clearance in 44% of subjects.19 At least a 50% improvement was achieved in 52% of patients. While only 59% of the patients continued medication usage during the optional treatment period, all subjects continued to improve during this time.

Topical tacrolimus was shown to be as effective as mometasone furoate 0.1% ointment in the treatment of dyshidrotic palmar eczema.20 After a 2 week washout period, 16 patients were randomized to apply 1 of the 2 study drugs to either a palm or sole twice daily for 4 weeks. There was a comparable reduction in dyshidrotic area and severity index (DASI) scores for both study drugs when used to treat palmar eczema. However, mometasone furoate was superior to tacrolimus in the treatment of plantar eczema. For time to relapse after the active treatment phase, no difference was noted between the 2 agents.

In a multicenter, randomized, vehicle controlled trial, the effectiveness of 1% pimecrolimus cream (Elidel®, Novartis) compared with vehicle was evaluated for the treatment of chronic hand dermatitis.21 Two hundred and ninety-four patients with chronic hand dermatitis of varied and mixed types were randomized to receive either vehicle or 1% pimecrolimus cream twice daily using occlusion at night. At the conclusion of the trial, on day 22, there was a trend toward greater clearance in the pimecrolimus group. Almost 28% of pimecrolimus-treated patients vs. 18% of vehicle-treated patients were clear or almost clear at the end of the study. Irritant contact dermatitis and dorsal hand involvement showed the most favorable response.

In an open-label, uncontrolled study, pimecrolimus 1% cream, applied twice daily with occlusion at night, showed favorable response for hand eczema in 85% of patients (n=12) at 3 weeks. The drug was well tolerated and measurement of pimecrolimus blood levels indicated low systemic exposure.22

Given the chronic nature of hand eczema, topical calcineurin inhibitors may provide the greatest benefit as a maintenance therapy between flares, which is akin to that adopted for the treatment of atopic dermatitis. Based on the information derived from a small number of studies, their use appears to be limited to treatment of non-hyperkeratotic hand eczema.20-22

Retinoids

Bexarotene (Targretin®, Eisai) is a new synthetic retinoid which, in both topical and systemic forms, has been studied in the treatment of cutaneous T-cell lymphoma. In a phase 1-2 trial, 1% bexarotene gel was evaluated for safety, tolerability, and efficacy in the treatment of severe chronic hand dermatitis.23 Fifty-five patients were randomized to receive treatment with either bexarotene gel alone or in combination with topical 0.1% mometasone furoate ointment or with 1% hydrocortisone ointment. Bexarotene was initially applied every other day and increased in a stepwise approach to 3 times daily as tolerated. Topical steroids were applied twice daily. Patients were evaluated regularly during the 22 week treatment period and then 4 weeks post treatment. Forty-two of 55 patients completed the study with 36% of all patients showing more than 90% clearance, and 71% showing at least a 50% improvement. The response rates in the 3 treatment groups were not statistically different. The drug was well tolerated by most patients; however, there was a 30% incidence of irritation in all treatment arms.

Phototherapy

Phototherapy is one of the most effective treatments for hand eczema.

Ultraviolet B (UVB)

Narrow band UVB therapy has shown clinical efficacy in the treatment of psoriasis and atopic dermatitis.24 However, there is little information about its role in the management of hand eczema.

The safety and efficacy of narrow band UVB therapy for the treatment of chronic hand eczema (dry and dyshidrotic types) was evaluated in a randomized, controlled, prospective study of 15 patients who had failed conventional topical therapy.25 Patients were treated with narrow band UVB (NBUVB) on 1 hand and topical photochemotherapy using 0.1% 8-methoxypsoralen (8-MOP) gel on the other 3 times weekly for 9 weeks. Patients were assessed every 3 weeks during the treatment period and then evaluated 10 weeks following the last treatment. All of the 12 subjects who completed the trial showed improvement noting no statistical difference between modalities.

Both broad band and narrow band UVB appear to be as effective as topical/bath psoralen + UVA (PUVA) therapy in the treatment of chronic hand dermatitis.26 However, the risks of phototoxicity and dyspigmentation associated with local PUVA therapy make UVB therapy a preferable initial therapeutic option.

PUVA

Several studies have reported benefits from both topical and systemic PUVA therapy for chronic hand dermatitis.27-29 PUVA may be the phototherapy of choice for hyperkeratotic hand eczema given the ability for the UVA’s longer wave lengths to penetrate deeper into the skin.

There appears to be little difference in efficacy between topical and systemic PUVA. In a retrospective study on localized topical and systemic photochemotherapy for chronic hand and foot dermatoses, Hawk and Grice30 noted no difference in efficacy between these modalities in their treatment of 40 patients.

However, the study population was mixed, with some patients having chronic eczema, while others had palmo-plantar pustulosis and psoriasis. A more recent open-label, randomized, controlled trial compared the efficacy of home administered oral PUVA with hospital delivered bath PUVA for chronic hand dermatitis in 150 patients.29 The investigators found no difference between treatment groups at the end of 10 weeks of treatment and at follow-up 8 weeks later.

UVA-1

UVA-1 therapy has been established as an effective treatment of atopic dermatitis in several clinical trials.31,32 UVA-1 was first reported to be beneficial for dyshidrotic hand eczema in an uncontrolled trial of 12 patients.33 Subjects received daily treatment with local UVA-1 irradiation at a dose of 40 J/cm2 for 3 weeks. Eczema severity was evaluated using the DASI. Conditions for 10 out of 12 patients were judged to be cleared or almost cleared at the end of the treatment course and patients remained relapse free during a 3 month follow-up period. In a randomized, double-blind, placebo controlled trial, 28 patients with chronic dyshidrotic hand eczema were randomized to receive UVA-1 irradiation or placebo 5 times/week for 3 weeks. Change in DASI was the primary endpoint and patients were assessed weekly during the treatment phase and then at 3 and 6 weeks post treatment. Therapeutic response was noted in the treatment group at 2 weeks and a significant sustained reduction in DASI persisted at 6 weeks following the last treatment.

Ionizing Radiation

The inflammatory cells operative in eczema are highly radiosensitive.34 Grenz rays and superficial radiotherapy were popular treatments for chronic severe hand eczema 20-30 years ago. However, their association with a greater risk for carcinogenesis coupled with the introduction of megavoltage external beam photon and electron units, has resulted in these treatments falling out of favor. Superficial radiation therapy appears to provide greater benefit than Grenz ray therapy and this is likely because of its deeper penetration into the skin. As a result of non-standardized treatment protocols, it is difficult to critically compare studies and reach valid conclusions about these forms of treatment.35-39

In a recent case report, low dose external beam megavoltage therapy resulted in complete clearance and a prolonged remission of severe treatment resistant dyshidrotic hand eczema in a 41 year-old woman.40 These results are impressive and a reminder that ionizing radiation, an often forgotten intervention for this disease, may be helpful for refractory cases.

Systemic Treatments

Immunosuppressive Therapy

Systemic immunosuppressive therapy may be considered for those cases of hand eczema that are refractory to topical steroids and phototherapy. Systemic glucocorticoids are generally effective in managing acute flares; however, given their side-effect profile, they are not practical over the long-term. Similarly, the usefulness of cyclosporine for this condition seems limited to the short-term. While 1 study demonstrated prolonged disease remission in 74% of patients 1 year after a 6-week course of cyclosporine 3mg/kg/day,41 other studies have shown high relapse rates within weeks of drug discontinuation.42,43

Agents such as methotrexate and mycophenolate mofetil (CellCept®, Roche Laboratories) may be more promising for long-term control of severe hand eczema. Methotrexate has been shown to be an effective adjunctive agent in 5 patients with severe recalcitrant dyshidrotic eczema. Patients were treated with methotrexate 15-22.5mg/week and all were subsequently able to significantly reduce or eliminate systemic steroid use.44 In a case report of a 39 year-old male with severe dyshidrotic eczema, long-term control was ultimately achieved and maintained with mycophenolate mofetil 2-3gm/day. The drug was well tolerated without serious adverse effects after 1 year of treatment.45

Retinoids

Systemic retinoids, including etretinate (Tigason®, Hoffmann-La Roche) and acitretin (Soriatane®, Stiefel), have shown some benefit in the treatment of hand eczema.34,46 Studies in the past have focused on their treatment of hyperkeratotic eczema.

Alitretinoin (9-cis-retinoic acid) (Toctino®, Basilea Pharmaceuticals) is an oral retinoid that is capable of activating all retinoic acid receptors as well as retinoid X receptors. It is currently approved in Europe for the treatment of solid malignant tumors and as a new once-daily treatment for adults with severe chronic hand eczema unresponsive to potent topical corticosteroids. While it is not approved in North America, this agent, like its related compounds, has been evaluated for the treatment of chronic hand dermatitis.47 In a multicenter, randomized, double-blind, placebo controlled trial, 319 patients were allocated to receive either placebo or alitretinoin at 10mg/day, 20mg/day, or 40mg/day for 12 weeks. All types of hand dermatitis were included in the study, but the majority of patients had the hyperkeratotic type. Patients were deemed to be responders if, by physician’s global assessment, the dermatitis was clear or almost clear at the end of the treatment period. Of the 244 patients who completed the 12 week course, 127 were responders. Response rates increased across the dosage range and were 27% for the placebo group and 39%, 41% and 53% for the 10, 20 and 40mg/day groups, respectively. This incremental response rate was independent of the type of hand eczema. The drug was generally well tolerated and adverse events, such as headache, mucocutaneous dryness, photosensitivity, and dyslipidemia occurred more frequently with higher drug doses.

Botulinum Toxin

Hyperhidrosis has been reported to be an aggravating factor in dyshidrotic hand eczema in nearly 40% of cases.48 As such, botulinum toxin - type A (BTX-A), which is an approved treatment for axillary hyperhidrosis and an effective, commonly used treatment of palmar hyperhidrosis, has been explored as an off-label treatment for dyshidrotic eczema.49 In an open study of 10 patients with dyshidrotic hand eczema treated with 162 units of intradermal BTX-A in 1 hand only, 7 of 10 patients experienced good or very good improvement in their eczema on the treated hand at 6 weeks.50 Sweating was more likely to be an aggravating factor to the eczema in responders to this formulation.

BTX-A was found to be a very effective adjuvant treatment for dyshidrotic eczema in 6 patients, who were treated with topical steroids alone on 1 hand, and a topical steroid plus 100 units of intracutaneous BTX-A at week 0 in the other, more severely affected hand. There was a significantly greater drop in DASI scores in the combination treatment side with a stabilization of hand eczema at 8 weeks, whereas there was a 50% partial or complete relapse rate on the monotherapy side. Pruritus and vessiculation decreased more rapidly in the combination therapy side. The authors concluded that BTX-A inhibition of substance P release may be operative in these antipruritic effects.51

Iontophoresis

Hyperhidrosis, a recognized risk factor for hand eczema, generally responds well to treatment with tap water iontophoresis.52 In a randomized half-side study of 20 patients with mild-to-moderate dyshidrotic eczema, patients received steroid free topical therapy of both hands and daily unilateral tap water iontophoresis. Significant improvement in eczema, as assessed by DASI scores, was noted only in iontophoresis treated hands. The authors attributed improvement to a reduction in sweat secretion and possibly enhanced absorption of topical therapy.53

Conclusion

Hand eczema is a highly prevalent disorder, which in many patients is chronic, debilitating, and associated with impaired quality of life. Both endogenous and exogenous factors play a role in the development of the disease. Lifestyle management, the use of emollients, avoidance of allergens, and topical corticosteroids are effective and sufficient treatments for some patients, but many require additional intervention. The best way to manage these patients is unclear based on the current level of evidence. A standardized, universally accepted classification system of hand eczema and larger scale, well-designed, randomized trials are necessary prerequisites to achieve optimal and successful management of this disorder.

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In this issue:

  1. New and Existing Therapeutic Options for Hand Eczema
  2. Treatments for Pityriasis Rosea
  3. Update on Drugs and Drug News - March 2009