University of Groningen

Hand eczemaChristoffers, Wianda

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Chapter

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Discussion How to treat hand eczema in daily practice?

Wietske Andrea Christoffers

Department of Dermatology, University of Groningen,

University Medical Center Groningen, Groningen, Netherlands

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Overview of main findings & general discussionThis thesis discusses the various treatment options for patients with hand eczema.

In chapter 2 we reviewed extensively, according to the Cochrane protocol, all the random-

ized controlled trials (RCT) on interventions for hand eczema. The slightly disappointing

conclusion was that, with a few exceptions, the overall quality of the studies is poor and

head-to-head trials are lacking. A systematic review published in 2004 came to the same

conclusion.1 In spite of well-designed studies regarding alitretinoin and topical calcineurin

inhibitors, the evidence for the efficacy of topical corticosteroids or cyclosporine and acitre-

tin, often used in daily practice, has remained scarce.

Clinicians often wonder what treatment would be best for their specific patient with hand

eczema. The choice for an optimal treatment should, ideally, be based on a comparison be-

tween different treatment modalities, such as topical corticosteroids versus topical calcineu-

rin inhibitors. In chapter 3 we discussed questions from daily practice.

Here the overall conclusion was in line with that of chapter 2: in general, there is insuffi-

cient high-quality evidence to recommend one treatment over another. For example, PUVA

and UVB are both effective in the treatment of hand eczema, but there is no evidence of a

clinical advantage of one over the other. The same is true of topical calcineurin inhibitors;

although they are more effective than placebo, their superiority over topical corticosteroids

in cases of hand eczema has not been demonstrated. Oral retinoids (alitretinoin), however,

do appear to be effective and well tolerated in hand eczema, especially in hyperkeratotic

hand eczema. In chapter 2 we included a potentially important study by Schmitt et al. which

compared the effectiveness of cyclosporine to alitretinoin. Unfortunately, this investigator-

initiated study was ended prematurely due both to an insufficient number of naïve partici-

pants and to limited resources. These problems are characteristic for intervention studies

with patents: once a drug has been established in daily practice or has received market

authorization, there is no financial motivation for pharmaceutical companies to conduct a

comparative study. This could explain the scarcity of head-to-head trials.

Besides randomized controlled trials, daily life studies like chapter 4 provide useful informa-

tion. One advantage is the applicability of their results to daily clinical practice; therefore

the external validity is higher in daily life studies than in clinical trials, though the internal

validity is lower. Limitations in external validity make it difficult to apply results of clinical

trials in daily practice. Trials recruit only ‘perfect patients’ who fulfill strict in- and exclusion

criteria, are relatively healthy, motivated and adherent to treatment. In daily practice patients

are unselected: only patients with true contraindications are excluded from treatment.2 In

general the number of drop-outs due to adverse events is higher in daily practice than in

clinical trials. Differences in duration of active treatment may also contribute to the higher 10chapter

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discontinuation rates. Moreover patients who choose to participate in clinical trials are often

very motivated to fulfill the trial period despite adverse events.3 Finally, artificial endpoints

and a fixed duration of treatment might influence the external validity of RCTs. The end

points might not be relevant for a patient at all: for example, a reduction in erythema after

14 days of using tacrolimus might not be very relevant to a patient with a chronic condition

like hand eczema.4

For this reason, in chapter 4 we conducted a daily practice study regarding the drug survival

of cyclosporine. This study concluded that cyclosporine is a safe treatment for patients with

recurrent vesicular hand eczema and patients used it for an average of 10.3 months, which is

substantially longer than the average trial.

One of the first steps after diagnosing hand eczema is to provide education regarding the

use of emollients, gloves and the avoidance of allergens and irritants. Contact allergens such

as thiuram, mercaptams and acrylates are well known for their role in hand eczema. How-

ever, the role of contact allergies is an issue of debate in patients with chronic hand eczema.

In chapter 5 we studied the most frequent sensitizers in subjects with hand eczema. We

demonstrated that 50.3% of patients with clinical subtype chronic fissured hand eczema

were sensitized to at least one allergen in an extended European baseline series. This num-

ber was substantially higher than the sensitization rate in the general population, where the

median prevalence of contact allergy to at least one allergen is 21.2% (range 12.5–40.6%).5

In subjects with recurrent vesicular hand eczema this number was even higher: 55.2% of the

patients was sensitized to at least one allergen in the extended European Baseline series

and 17.0% of this clinical subtype was polysensitized.

In patients with pulpitis, acrylates were frequent sensitizers. Acrylates are in general known

to be potent sensitizers. In chapters 6 and 7 we describe two cases of hand eczema due to

acrylate contact allergy. In chapter 6 a process operator developed bullae on the hands and

knee due to contact with various acrylates, of which 1,6-hexanediol diacrylate and glycidyl

methacrylate were, among others, the main sensitizers. Subsequently, in chapter 7 we went

on to describe therapy-resistant hand eczema in a printer who worked with acrylates. A

rare contact allergy to isobornyl acrylate turned out to be the explanation for his persistent

hand eczema. Triggered by these cases we further studied our patients who were sensitized

to (meth)acrylates; 87.5% turned out to have a contact allergy of the hands. These findings

highlight the importance of (meth)acrylates in (occupational-related) hand eczema.

When conventional therapies do not give desired results, patients tend to search for alterna-

tives. One marketed alternative for the treatment of eczema is tea tree oil (melaleuca al-

ternifolia), a natural oil derived from the Australian Melaleuca Alternifolia. This oil is claimed

to have antibacterial, anti-inflammatory properties and to reduce histamine-induced skin

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inflammation.6-8 Because it is a natural product consumers assume it to be safe. However,

when tree tea oil oxidizes, several sensitizing degradation products are formed. Chapters 8

and 9 discussed one of these products, ascaridole; more than one third of our patients who

were sensitized to ascaridole suffered from hand eczema.

How to treat hand eczema in daily practice?In spite of our focus on different interventions for hand eczema, we have not been able to

give a one-off recommendation for the treatment of patients with this disease. Although,

a Dutch guideline for the treatment of hand eczema does not exist, various well-respected

international groups have proposed guidelines, including Canadian9, Danish10 and German11

guidelines and the British consensus.12 These all acknowledge the importance of (primary,

secondary and tertiary) prevention, avoidance strategies and education and propose that

treatment be tailor made to the needs of the specific patient. All guidelines go on to recom-

mend moderate to super potent topical corticosteroids. If the hand eczema is unresponsive

to topical corticosteroids, different guidelines give different recommendations, but the

potential options are often listed in alphabetic order without clear stratification. In this final

chapter of the thesis we aim to provide a clear, stratified, practical tool to treat hand eczema

based on current literature, existing guidelines and the findings of this thesis.

In chapter 1 we discussed the steps for diagnosing hand eczema and the differential diag-

nosis. We later in chapter 5 presented a flow chart to classify the clinical subtypes of hand

eczema according the criteria of Danish Contact Dermatitis Group. Once the diagnosis of

hand eczema and the clinical subtype have been established, the treatment of hand eczema

consists of several important steps as displayed in Fig. 1.

Immediate treatment is recommended and watchful waiting should be discouraged, since

various studies have demonstrated that the prognosis of chronic hand eczema is poor. Hald

et al. found in a 6-month follow up study that fissures and scaling, signs of chronic hand

eczema, had a poorer prognosis than, for example, vesicles.13 Meding demonstrated that

the extent of the hand eczema also influences the prognosis negatively.14 Since patients

experience a median patient delay of three months, and 11.2% of the patients wait longer

than one year before consulting a physician15, physicians should be prompt with proactive

treatment.

Basic skin care & protectionThe first step in the treatment of hand eczema is education and basic skin care advice. One

must emphasize that no quick and easy solution for hand eczema exists. As proper skin care 10chapter

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will not cure the eczema completely patients may fail to see its value, but skin care is vital

and patients should continue with it for the rest of their lives.

Patients need to know that frequent contact with irritants such as water, detergents and

cutting fluids can impair the skin barrier function. This impaired barrier function can evoke

or maintain hand eczema. Insight into potential triggers and the mechanism behind the

disease makes the patient self-reliant and increases self-management.16

Whenever possible, causative factors should be removed. Chapter 5 demonstrated that

about half of hand eczema patients are sensitized to at least one allergen. The clinician and

patient should try to establish whether this sensitization is relevant for the hand eczema,

though this could be a complex quest. Contact allergens that are clinically relevant for the

hand eczema can be present in cosmetic, household and occupational products; these

should be checked, and where necessary, avoided. Websites such as www.huidarts.com or

www.huidziekten.nl contain extensive lists of allergens with clear information as to potential

sources of allergens. The physician ought to provide the patient with specific written infor-

mation, since it is difficult to remember complex information like names of contact allergens.

Unfortunately, the complete elimination of a contact allergen does not guarantee complete

healing of the hand eczema, since hand eczema is typically a multifactorial disease.

A silent causative factor in hand eczema is frequent washing of the hands (>20 times a day).

If the hands are not visibly dirty but must be cleaned to prevent infection, as in the case of

health care workers, the use of alcohol-based disinfectants instead of traditional full hand

washing should be encouraged.17,18 If hands are visibly dirty, traditional hand washing is nec-

essary.19 Therefore lukewarm water and preferably a fragrance-free soap without well-known

sensitizers such as MCI/MI should be used. The hands should be dried well, preferably with

disposable paper towels, which have higher drying efficiency and are more hygienic than

(hot) air dryers or common-use towels.20 Subsequently, an emollient should be applied

immediately. One should avoid rings, especially when washing the hands, as dirt and soap

can get trapped under a ring, causing irritation; the skin underneath a ring is also difficult to

dry.21

Wet work in general is an important stressor for the skin and plays a prominent role in the

majority of irritant hand eczema cases. Whenever possible, wet work should be avoided, for

example by using a washing machine and a dishwasher. Protective (household) gloves can

also be worn, but gloves be worn in the correct way.

Gloves are essential in the avoidance of contact with allergens and irritants. Different gloves

are suitable for different purposes. It is important to select a specific glove for a specific job,

since gloves might provide good protection against one substance but be easily penetrated

by another.22 Moreover, gloves may themselves contain sensitizers which should be avoided.

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Nitrile gloves provide good protection against solvents, oils, greases, selected acids •and bases. These gloves can contain common sensitizing rubber accelerators such as

carbamates, thiurams, and mercaptams.

Vinyl gloves protect against acids, bases, oils, greases, peroxides, and amines. These •gloves might contain the rare sensitizers phthalates and bisphenol A and are not very

elastic.

Latex gloves provide proper protection against biological and water based materials. •These gloves can contain common sensitizing rubber accelerators such as carbamates,

thiurams, and mercaptams. Moreover, latex gloves can cause a protein contact dermati-

tis or an immediate type I allergic reaction.

Polychloroprene gloves protect against acids, bases, alcohols, fuels, peroxides, hy-•drocarbons, oils, greases, and phenols. Polychloroprene gloves might contain the rare

sensitizer thioureas.

Polyvinyl alcohol gloves protect against aromatic and chlorinated solvents, ketones, •esters and methacrylate. These gloves are quite expensive.

Butyl gloves protect against ketones, aldehydes and esters. These gloves are also •expensive.

Multilayer laminated gloves (laminated gloves of ethylene- vinyl-alcohol-polyethylene, •4H®) protect against practically everything, but their fit is poor.22

As discussed in chapters 5, 6 and 7, acrylates are well known sensitizers. Multilayer laminat-

ed gloves provide the best protection against acrylates;23 however these gloves have a poor

fit and are not practical for fine manual work like that of nail stylists and dental technicians.

In such cases thicker nitrile gloves are more effective than latex or vinyl gloves because of

their longer breakthrough time for various acrylates. Their elasticity is also superior to that of

multilayer laminated gloves.23-26

Not only must patients select the proper gloves, but they must wear gloves only for a short

period of time and not re-use them. The barrier function of a glove is impaired after the first

contact with an allergen, whether or not the glove has been worn. One should immediately

discard gloves with holes and regularly replace all gloves. Moreover, when putting gloves

on or off, a subject can come into contact with the, often contaminated, outer lining of the

glove and transfer the allergen from the outside to the inside of the glove. Selection of

proper gloves remains challenging, since besides exposure to allergens and irritants, one

must also consider the risk of latex allergy and sensitization to rubber chemicals. Additional

information regarding gloves can be found on http://www.ansell.nl/, http://www.kcl.de/ and

http://www.marigoldindustrial.com/. We also recommend contacting the occupational physi-

cian. Another point to consider is that although gloves protect the skin from contact with

allergens and irritants (especially wet work), the occlusion of the skin caused by the glove

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itself is a risk factor for hand eczema.22,27 Therefore, cotton linings or inner gloves underneath

occlusive gloves are recommended when gloves are worn for longer than 10 minutes.28 In

conclusion, gloves must be worn as long as necessary, but as short as possible.

Patients should be instructed to use emollients frequently. Lipid-rich emollients (ointments)

are preferred over creams: because these are more lipid and contain less water, thus there is

less evaporation. Moreover, creams more often contain sensitizing preservatives and mildly

irritating emulsifiers. The Cochrane review (chapter 2) demonstrated that a petrolatum-

based emollient (Vaseline lanette) did not differ from a ceramide-containing emollient

(Locobase® Repair).

However, one must consider not only the efficacy of an emollient but, even more important,

the patients’ preference. Patient-rated factors such as cosmetic acceptability, odor, greasi-

ness and amount of staining should therefore be taken into account. Providing various alter-

natives during the first visit allows the patient to select the emollient of his personal prefer-

ence, which could contribute to his adherence. Patients must be instructed to use emollients

several times a day, especially after contact with water. Multiple samples should be available

in several places in the house, as next to every sink, or in a handbag. The patient must

understand the use of emollients and that emollients must be applied to the entire hands,

including web spaces, finger tips and the back of the hands.21

Topical treatmentTopical corticosteroids are the mainstream treatment for hand eczema. The rationale for

topical corticosteroids is based largely on pharmacological reasoning and clinical experi-

ence; actual evidence is limited. Nine randomized controlled trials with topical corticos-

teroids were carried out with hand eczema patients. These studies had different designs;

different corticosteroids and different vehicles, dosages or application frequencies were

used. It is thus difficult to compare and recommend an evidence-based dosing regime. To

prevent chronicity of hand eczema, we recommend as first treatment step a potent topical

corticosteroid, applied once or twice daily. To treat one entire hand, one fingertip unit (0.5

gram) of topical corticosteroids should be applied.29 Patients should be instructed not to

apply corticosteroids at the same time as their emollients, since this might diminish the total

dosage.

If after two to four weeks a potent topical corticosteroid seems to be insufficient, one should

evaluate the patient’s adherence to treatment. This should be discussed openly, since treat-

ment adherence to topical therapy is even poorer than to oral therapy.30,31 In a small study,

10 patients with moderate to severe atopic dermatitis were instructed to apply fluocinonide

0.1% cream twice daily for 5 days.32 The median treatment adherence was only 40% (range

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0-100). For treatments with longer durations, the adherence might diminish even further.

To improve treatment adherence, the dosage schedule should be easy to comprehend and

follow. Therefore a once daily application is preferable to a twice daily application, and com-

plex tapering schedules should be avoided. Although little studied, the correct way of taper-

ing is an issue of debate. Given the reservoir function of the epidermis, application every

other day might be preferred over application on three or four successive days. During the

tapering phase, the patient should be reminded to continue with frequent use of emollients.

Lack of information and (irrational) fear of adverse events can diminish treatment adherence.

Patients may suffer from corticophobia due to fear of skin atrophy and systemic effects.33

However, a systematic review of atopic dermatitis reported that randomized controlled trials

had shown no evidence for the development of skin atrophy provided that the corticoster-

oids were used appropriately.34 Full body application of very potent corticosteroids such as

clobetasol propionate does result in inhibited cortisol production in patients with severe

atopic dermatitis or bullous pemphigoid; however these effects disappeared with dosages

of less than 50 mg a week and with less potent corticosteroids.35,36

Thus the risk of systemic effects in the topical treatment of hand eczema was found to be

negligible. This, combined with the poor prognosis of chronic hand eczema, should encour-

age physicians to prescribe potent topical corticosteroids in an early phase. If topical cor-

ticosteroids are necessary over a longer time period, for example during the maintenance

phase, one can consider rotation with less potent topical corticosteroids or topical calcineu-

rin inhibitors (tacrolimus and pimecrolimus).

Other potential explanations for ineffectiveness of topical treatment are contact allergies

to lanolin or corticosteroids. This can be the case especially in hand eczema that worsens

despites adequate topical treatment, or if the eczema is more active in the borders than in

the center of the lesion (after ruling out dermatomycosis). In case of lanolin-sensitizations,

one must prescribe lanolin-free emollients (unguentum leniens (koelzalf FNA), paraffin, Vase-

line and Vaseline album) and lanolin free corticosteroids (Emovate, Elocon, and Dermovate

among others.37-39 Diagnosing a contact allergy to corticosteroids can be difficult, since the

patch test with corticosteroids suppresses the delayed type reaction by the anti-inflammato-

ry action of the corticosteroids themselves. When patch testing, one should at least test the

screening markers tixocortol pivalate, budesonide and hydrocortisone-17-butyrate, along

with the patient’s own corticosteroids.40 A day-7 reading can be introduced to pre-empt late

reactions to corticosteroids, but even this cannot exclude false-negative reactions. Corti-

costeroids are known to cross-react, based on C16-methylated and non-methylated mol-

ecules.41,42 Recommending a safe topical corticosteroid can be difficult.42,43 However, topical

calcineurin inhibitors are a valuable treatment alternative for every patient with a sensitiza-

tion to corticosteroids.10chapter

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The Cochrane review demonstrated that topical calcineurin inhibitors are comparable to or

more effective than placebos, but they are not more effective than mometasone furoate.44,45

Moreover, topical calcineurin inhibitors are almost seven times as expensive as topical cor-

ticosteroids (on average €12 versus €80 per 100 gram). Finally, long term adverse events are

not yet known, as long-term studies in atopic dermatitis are still in progress.

A further suggestion is to add salicylic acid to the treatment for patients with hyperkeratotic

hand eczema and water baths for patients with recurrent vesicular hand eczema, though

these recommendations are based purely on experience and not on evidence.

If topical treatment is successful after initial crisis intervention, one should switch to the

maintenance phase. Frequent application of topical corticosteroids should be tapered in an

easy to follow schedule and the patient should be encouraged to continue the application

of emollients. If tapering of corticosteroids results in a flare, one can prescribe short bursts of

potent topical corticosteroids or longer term continuous application of less-potent corticos-

teroids. One can also consider using rotation with topical calcineurin inhibitors instead of

maintenance therapy with topical corticosteroids.

PhototherapyWhen potent corticosteroids have failed to help patients with vesicular hand eczema one

should, before starting systemic treatment, consider phototherapy. Clinical experience has

also shown phototherapy to be effective in treating chronic fissured hand eczema. The

effectiveness of topical PUVA in treating hyperkeratotic palmar eczema might be less,

however, probably because of the thick hyperkeratotic plaques and the absence of

inflammation.

In Chapter 2 we demonstrated that phototherapy was more effective than placebo, but

there was little evidence to indicate which method, either UV-B or PUVA was superior.

If frequent visits to the hospital are feasible and the travel distance to the hospital is accept-

able, one can prescribe phototherapy, although several treatment centers may decide to

skip this treatment option. First of all, phototherapy needs to be tailored to specific patients

and clinics. Moreover, although it is effective, phototherapy has drawbacks. Studies of

psoriasis patients concluded that patients found phototherapy demanding and time

consuming and some even doubted the therapeutic value of the time they had invested.46

Moreover, frequent hospital visits resulted in considerable direct and indirect costs and

absence from work.47 Phototherapy at home could resolve some of these issues: in patients

with chronic hand eczema oral PUVA with a portable tanning unit at home is as effective as

hospital-administered bath PUVA and more cost-effective.48 In the Netherlands, the main

disadvantage of phototherapy at home is the uncertainty of reimbursement.

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Fig. 1: Flowchart for the treatment of a patient with moderate to severe hand eczema.The flow chart is based on the current level of evidence and clinical experience. The timeline in the upper part of the flow chart is just an indication of recommended treatment duration.

Systemic interventions for hand eczemaBefore starting systemic therapy for hand eczema, one must re-evaluate the patient’s

treatment adherence and reconsider the diagnosis.

The decision to start systemic treatment should be made by both physician and patient,

taking into consideration possible adverse events, benefits and costs for the specific patient.

Patients should be given verbal and written information regarding the systemic options and

offered sufficient time to consider these options.

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In the Netherlands, alitretinoin is the only registered systemic treatment option for chronic

hand eczema. In well-designed pharmaceutical sponsored trials49-51 30 mg alitretinoin a day

resulted in clear or almost clear responses in 48% of the participants, compared to 17%

with a placebo.50 In the hyperkeratotic subtype 49% reacted, as compared to 12% in the

placebo group. However, only one third (33%) of the participants with recurrent vesicular

hand eczema (defined in the study as pompholyx) reached clearance or almost clearance, as

compared to 16% in the placebo group.

Based on these statistics and the mechanism of alitretinoin, and the fact that alitretinoin is

the only registered treatment option for hand eczema, we recommend alitretinoin as the

first systemic intervention step for all types of chronic hand eczema, except for recurrent

vesicular hand eczema (Fig. 1). A dosage of 30 mg/day should be prescribed. If there is no

considerable improvement after 12 weeks, alitretinoin should be stopped. Otherwise it can

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be continued until 24 weeks. After 24 weeks of treatment, according to the manufacturer’s

guidelines the patient should stop with alitretinoin. In case of an exacerbation, alitretinoin

can be restarted.

If alitretinoin is insufficient, acitretin 25 mg/day is a valuable alternative for hyperkeratotic

hand eczema. For other clinical subtypes of hand eczema cyclosporine can be considered.

For patients with recurrent vesicular hand eczema a low dose of oral cyclosporine might be

preferred over alitretinoin. As demonstrated in chapter 4, the drug survival of cyclosporine

was especially long for patients with recurrent vesicular hand eczema, and more than half of

the patients achieved an improvement of at least 50%. Meta-analysis in patients with atopic

dermatitis demonstrated an efficacy of cyclosporine of 55% after 6 to 8 weeks.52 In patients

with atopic dermatitis, starting with a high dose of cyclosporine (>3.5 mg/kg/day) and sub-

sequent tapering of the dose (drop-down) seemed more effective and resulted in a longer

drug survival than starting with a low dose of <3.5 mg/kg/day and slowly increasing the

dose to reach the optimum treatment effect (step-up).53 Moreover, in chapter 4 we demon-

strated that cyclosporine can be used safely for several months to years and only one patient

discontinued treatment because of an increase in serum creatinine levels. Unpublished data

demonstrate the same; atopic dermatitis patients whose median treatment duration was

more than one year experienced no substantial influence on renal function.53

After 6 weeks one should evaluate the effect of cyclosporine; if this is satisfactory, the drug

can be continued for 3-6 months as needed. Even longer treatment did not seem to result in

more adverse events and can therefore be considered for refractory cases. During treatment

with cyclosporine, one must carefully monitor blood pressure and serum creatinine, among

others.

If cyclosporine is not effective, one can then consider alitretinoin for patients with recurrent

vesicular hand eczema.

If alitretinoin, acitretin and cyclosporine are ineffective, various other off-label treatment

options are available. Methotrexate (10-15 mg/week) with folic acid may be beneficial in

hyperkeratotic hand eczema54, while azathioprine (50-150 mg/day) can be effective in

recurrent vesicular hand eczema and chronic hand eczema. 55,56

For severe refractory chronic or vesicular hand eczema, unresponsive to conventional

treatment, mycophenolate mofetil (0.5-3 gram/day),57 enteric-coated mycophenolate sodium

(720 mg twice a day),58 or a low-dose of prednisolon (5-10 mg/day) with osteoporosis pro-

phylaxes can be prescribed, though there is no evidence for the effects of these treatment

options in patients with hand eczema. Furthermore, based on experience, a course of the

oral antifungal agent itraconazol occasionally seems effective for recurrent vesicular hand

eczema. If a subject is prone to superimposed infections of the skin this may aggravate the

hand eczema; long-term treatment with oral claritromycin (500 mg/day) can then be

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considered. For hyperkeratotic palmar eczema dithranol and coal tar can be prescribed.

Combinations of different oral treatments can be considered in extreme refractory cases,

though this should be done with extreme caution and careful monitoring. In the future,

biologicals may provide alternative options, though to date no effective biological for (hand)

eczema is known.

The ESCD Guideline: Guidelines for diagnosis, prevention and treatment of hand eczemaAn expert working group of the European Society of Contact Dermatitis (ESCD) is currently

working on a guideline for the diagnosis and treatment of hand eczema59, partly based on

the findings of the Cochrane review from chapter 2.

Overall, the guideline of the ESCD does not differ essentially from our flow chart.

The skin protection program of the ESCD with regards to gloves, hand washing and

emollients overlaps with the advices described in the text above.

The ESCD strongly recommends quick and vigorous treatment to avoid the development

of chronic hand eczema. The use of topical corticosteroids is the first line treatment in the

management of hand eczema (evidence of high quality, strong consensus-based recommen-

dation), but states a maximum duration of six weeks.

For patients with chronic hand eczema refractory to topical corticosteroids, the ESCD

strongly recommends alitretinoin (high quality evidence, consensus-based recommendation)

or photo-therapy (UVB, PUVA) (evidence of moderate quality, strong consensus-based

recommendation). We have positioned phototherapy at the same level as the ESCD.

The ESCD emphasizes that other treatment options are off-label. The off-label use of

cyclosporine is recommended as alternative option by the ESCD (evidence of moderate

quality, strong consensus-based recommendation). Other options such as azathioprine,

acitretin or methotrexate can be considered once other therapeutic options have failed.

A substantial difference between the ESCD guideline and our treatment plan is the inclu-

sion of specific subtypes of hand eczema in our treatment plan. The ESCD emphasizes that

in research and clinical trials some kind of classification needs to be applied, though current

consensus is lacking. Thereupon the ESCD proposes to use the classification system of

Diepgen et al.60 This classification, as discussed in chapter 5, includes a mixture of

etiological and clinical types.

In the guideline of the ESCD the classification of subtypes is not further incorporated to

recommend specific treatment options to specific subgroups of hand eczema. Our flow

chart distinguishes clinical subtypes of hand eczema according to classification of the

Danish contact Dermatitis Group.10 Because of this classification, we slightly differ from the

guidelines of the ESCD. Alitretinoin is a highly appreciated treatment option for the most

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subtypes of hand eczema. However, in our opinion, alitretinoin should not be preferred for

recurrent vesicular hand eczema, but we recommend the use of cyclosporine. This can be

considered as a controversial statement given the level of evidence for alitretinoin.49-51,61

In addition, cyclosporine is not registered for the treatment of hand eczema, only for the

treatment of atopic dermatitis. However, based on clinical experience, the findings in

chapter 4 and the limited efficacy of alitretinoin in clinical trials in this subtype, we consider

this justified. Though, further studies are needed.

Future perspectivesThis thesis demonstrates various hiatuses in our knowledge regarding hand eczema. First,

there is no consensus regarding the definition of hand eczema and the classification of its

subtypes. The textbook definition of hand eczema is “noninfectious skin inflammation of the

hands”. For chronic hand eczema Diepgen’s definition is widely accepted: “hand eczema

which exists for more than three months or which returns twice or more within 12 months

despite adequate dermatological therapy and patient compliance.”11 In chapter 2 we

encountered various time slots for the definition of ‘chronic’, such as six weeks or six months.

International consensus regarding this last definition is important in order to improve unifor-

mity in clinical trials. However, the differences in the definition of chronic hand eczema seem

relatively insignificant compared to the lack of consensus regarding classification of subtypes

of hand eczema. Several contradicting articles have been published. 60,62,63 Some groups use

etiological subtypes, others clinical, and still others a combination of etiological and clinical

subtypes. We would like to recommend the clinical classification as described by the Danish

Contact Dermatitis Group,10,62 though slightly adjusted. We would include a more detailed

description of the clinical subtype ‘chronic fissured dry hand eczema’ since, as reported

in chapter 5, a wide range of different morphological types can be included under this

subtype. The tool in chapter 5 includes the localization on the hand and the morphology,

which results in a clinical diagnosis. This tool should be expanded with the factor ‘time’ to

distinguish chronic from acute hand eczema and to further determine the nature of recurrent

vesicular hand eczema. This could be an important step toward consensus regarding these

subtypes.

In the Cochran review we encountered first of all a wide range of systems for scoring

severity of the disease, and newer and improved scoring systems are still being developed.

Weistenhöfer et al. demonstrated a maze of different, often unvalidated, scoring systems: 45

different methods for quantifying hand eczema were identified in 69 articles.64 The different

scoring systems included either the extent of the hand eczema, the morphological char-

acteristics, subjective criteria, or a combination of these. Moreover, for the majority of the

scoring systems, inter and intra observer reliability were not studied.

To reach a consensus regarding the scoring of severity we would advocate the approach

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of OMERACT (Outcome Measures in Rheumatology) 65 and HOME (Harmonizing Outcome

Measures for Eczema).66 The HOME initiative aims to facilitate an international, multidisci-

plinary consensus on core outcome measures to be included in all eczema trials and clinical

record keeping: it also aims to identify other relevant issues for eczema outcome research.

The use of standardized endpoints in randomized controlled trials and in observational

studies is vital in that it facilitates comparisons of outcomes across studies in different study

populations, which as we learned in chapter 2 is frankly impossible in current studies.

Moreover, a minimal set of outcome measures would improve the quality of studies

overall; some studies included in chapter 2 used outcomes which were barely relevant in

daily practice.

Consensus regarding the definition of hand eczema and its subtypes, and the development

or recommendation of a single severity scoring system are essential for evidence based

medicine.

A second important observation of the Cochrane review was the lack of well-designed

randomized controlled trials comparing major treatment groups. We therefore present an

urgent appeal for such studies.

At the time of writing, alitretinoin is, in the Netherlands, the only registered treatment for

chronic hand eczema. Other treatment options such as cyclosporine or acitretin are used

off-label. In clinical trials alitretinoin was effective in the majority of hand eczema patients,

though it is effective only in 33% of patients with vesicular hand eczema. Based on the

findings of chapter 4, cyclosporine might be more effective in patients with recurrent

vesicular hand eczema. Therefore we would like to propose a clinical trial which compares

the efficacy of alitretinoin and cyclosporine. Schmitt designed such a trial and registered it at

clincialtrials.gov. This trial aimed to compare the efficacy and safety of cyclosporine and

alitretinoin in the treatment of severe atopic hand dermatitis. Although unfortunately this

study was ended prematurely because of the inability to include a sufficient number of

patients, the need for such research is obvious.

The perfect study would compare the efficacy of cyclosporine and alitretinoin in different

clinical types of chronic hand eczema, starting with recurrent vesicular hand eczema, since

a relatively large number of patients suffer from recurrent vesicular hand eczema and this

group seems to benefit the least from alitretinoin.

The study should include proper outcome measures. The primary outcome would preferably

be an objective observer-rated severity score, such as the HECSI. Patient-rated outcomes

should be included prominently in the secondary outcomes. Quality of life is an important

subjective outcome parameter. The DLQI seemed to correlate with the HECSI67, though a

scoring system specific for hand eczema patients would be preferred. Recently, an interna-

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tional group of experts developed the German Quality of Life in Hand Eczema Question-

naire (QOLHEQ).68 The QOLHEQ scores the health related quality of life for hand eczema

patients in different domains (symptoms, emotions, functioning, and treatment) and is

currently being translated into Dutch. This instrument will be a valuable addition to the

existing dermatological quality of life scoring systems such as the SKINDEX and the DLQI.

Further, other patient-rated outcomes such as itching, loss of sleep and productivity loss

should be included. The number and severity of adverse events should be registered

throughout the study. Finally, we highly recommend a cost-effectiveness analysis, including

health care costs and patient expenses (absence from work, out-of-pocket expenses).69

The study would require a minimum duration of 24 weeks, since hand eczema is a chronic

relapsing condition.

During the study, all participants would be advised to continue the use of emollients.

One of the main difficulties Schmitt encountered in his study was the lack of naïve patients

(patients who had never before received alitretinoin or cyclosporine). However, as demon-

strated by the multivariate analysis in chapter 4, being naive does not significantly influence

the outcome of the systemic therapy. Moreover, the majority of our patients received

multiple episodes of systemic therapy, and the effectiveness during a second or third

episode is not necessarily better or worse in the following episodes. The requirement to

include naïve patients can therefore be negated, or the study could be conducted in a

multicenter setting to achieve a substantial number of patients. Including a sufficient

number of patients is important in order to draw valid conclusions with sufficient statistical

power. The majority of the studies in the Cochrane review did not, however, include a

sample size rationale. The sample size calculation is usually based on the power (ß = 80 or

90%), the level of significance (α = 0.05) and the expected difference in the primary outcome

of the study. To do so, consensus regarding the primary outcome and the clinical relevant

difference is necessary. Reports on the study should adhere to the updated CONSORT

(Consolidated Standards of Reporting Trials) statement. 70,71 The CONSORT statement pro-

vides a checklist of 25 items which should be reported for each randomized controlled trial.

Such reporting facilitates complete and transparent reporting of trials and aids in

critical appraisal and interpretation. Observational studies should be reported according to

the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology)

statement.72

Several questions remain unanswered, including: a comparison between alitretinoin and

cyclosporine; a comparison of various potencies of topical corticosteroids and the taper

regime; a comparison between phototherapy and potent topical therapy; and so on. We are

also still waiting for long-term results of studies regarding counseling and education. With

regard to intervention studies, much remains to be explored.

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Not only interventions, but also the causality of hand eczema needs more attention in the

research. Studies of its genetic makeup should be included. Thyssen et al. took the first

steps with their research into the association between xerosis, atopic dermatitis, hand

eczema and contact sensitization, and filaggrin gene mutations. 73-75 Filaggrin mutations

are known for their role in atopic dermatitis and skin barrier dysfunction, and seemed to

be associated with the chronic dry fissured type of hand eczema. Moreover, hand eczema

in patients with atopic dermatitis and filaggrin null mutations had an earlier onset and was

more persistent (OR 2.98; 95% confidence interval 1.27-7.01) than in controls.76 We currently

lack studies regarding the distinct groups of hyperkeratotic palmar eczema and recurrent

vesicular hand eczema; however, since large population based studies are being conducted

and gene mapping is a developing area, in the next few years the genes responsible for

these specific subtypes may be revealed.

Several times in this thesis we have emphasized the need for better definitions of subtypes;

one of these subtypes is hyperkeratotic palmar eczema. Hyperkeratotic eczema could be

caused by repeated trauma or a dysfunction in keratinisation, but the exact mechanism is

unknown.77 Further studies into the histology and pathophysiology of this eczema might

provide insight into this mechanism and whether hyperkeratotic palmar eczema is truly a

form of hand eczema or something entirely different.

In this thesis I would like to advocate setting up well-designed randomized controlled trials

of at least 24 weeks in order to compare different treatment groups. The quality of such

studies would greatly benefit from more precise definitions of the types of hand eczema and

their clinical subtypes. For this purpose international consensus is indispensable.

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ReferencesVan Coevorden AM, Coenraads PJ, Svensson A, Bavinck JN, Diepgen TL, Naldi L, 1. et al.

Overview of studies of treatments for hand eczema-the EDEN hand eczema survey. Br J Dermatol

2004:151:446-451.

Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial 2.

apply?” Lancet 2005:365:82-93.

Andrade SE, Walker AM, Gottlieb LK, Hollenberg NK, Testa MA, Saperia GM, 3. et al. Discontinuation

of antihyperlipidemic drugs--do rates reported in clinical trials reflect rates in primary care settings?

N Engl J Med 1995:332:1125-1131.

Pacor ML, Di Lorenzo G, Martinelli N, Mansueto P, Friso S, Pellitteri ME, 4. et al. Tacrolimus

ointment in nickel sulphate-induced steroid-resistant allergic contact dermatitis. Allergy Asthma

Proc 2006:27:527-531.

Thyssen JP, Linneberg A, Menné T, Johansen JD. The epidemiology of contact allergy in the 5.

general population--prevalence and main findings. Contact Dermatitis 2007:57:287-299.

Koh KJ, Pearce AL, Marshman G, Finlay-Jones JJ, Hart PH. Tea tree oil reduces histamine-induced 6.

skin inflammation. Br J Dermatol 2002:147:1212-1217.

Wallengren J. Tea tree oil attenuates experimental contact dermatitis. 7. Arch Dermatol Res

2011:303:333-338.

Carson CF, Riley TV. Safety, efficacy and provenance of tea tree (8. Melaleuca alternifolia) oil.

Contact Dermatitis 2001:45:65-67.

Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, 9. et al. Canadian hand

dermatitis management guidelines. J Cutan Med Surg 2010:14:267-284.

Menné T, Johansen JD, Sommerlund M, Veien NK, Danish Contact Dermatitis Group. Hand 10.

eczema guidelines based on the Danish guidelines for the diagnosis and treatment of hand

eczema. Contact Dermatitis 2011:65:3-12.

Diepgen TL, Elsner P, Schliemann S, Fartasch M, Kollner A, Skudlik C, 11. et al. Guideline on the

management of hand eczema ICD-10 Code: L20. L23. L24. L25. L30. J Dtsch Dermatol Ges 2009:7

Suppl 3:S1-16.

English J, Aldridge R, Gawkrodger DJ, Kownacki S, Statham B, White JM, 12. et al. Consensus

statement on the management of chronic hand eczema. Clin Exp Dermatol 2009:34:761-769.

Hald M, Agner T, Blands J, Veien NK, Laurberg G, Avnstorp C, 13. et al. Clinical severity and prognosis

of hand eczema. Br J Dermatol 2009:160:1229-1236.

Meding B, Wrangsjo K, Jarvholm B. Hand eczema extent and morphology--association and 14.

influence on long-term prognosis. J Invest Dermatol 2007:127:2147-2151.

Hald M, Agner T, Blands J, Johansen JD, Danish Contact Dermatitis Group. Delay in medical 15.

attention to hand eczema: a follow-up study. Br J Dermatol 2009:161:1294-1300. 10chapter

235

Mollerup A, Johansen JD, Thing LF. Knowledge, attitudes and behaviour in everyday life with 16.

chronic hand eczema: a qualitative study. Br J Dermatol 2013:169:1056-1065.

Boyce JM, Kelliher S, Vallande N. Skin irritation and dryness associated with two hand-hygiene 17.

regimens: soap-and-water hand washing versus hand antisepsis with an alcoholic hand gel.

Infect Control Hosp Epidemiol 2000:21:442-448.

Slotosch CM, Kampf G, Loffler H. Effects of disinfectants and detergents on skin irritation. 18.

Contact Dermatitis 2007:57:235-241.

Pittet D, Allegranzi B, Boyce J, World Health Organization World Alliance for Patient Safety First 19.

Global Patient Safety Challenge Core Group of Experts. The World Health Organization

Guidelines on Hand Hygiene in Health Care and their consensus recommendations.

Infect Control Hosp Epidemiol 2009:30:611-622.

Huang C, Ma W, Stack S. The hygienic efficacy of different hand-drying methods: a review of the 20.

evidence. Mayo Clin Proc 2012:87:791-798.

Agner T, Held E. Skin protection programmes. 21. Contact Dermatitis 2002:47:253-256.

Kwon S, Campbell LS, Zirwas MJ. Role of protective gloves in the causation and treatment of 22.

occupational irritant contact dermatitis. J Am Acad Dermatol 2006:55:891-896.

Andersson T, Bruze M, Björkner B. In vivo testing of the protection of gloves against acrylates in 23.

dentin-bonding systems on patients with known contact allergy to acrylates. Contact Dermatitis

1999:41:254-259.

Rietschel RL, Huggins R, Levy N, Pruitt PM. In vivo and in vitro testing of gloves for protection 24.

against UV-curable acrylate resin systems. Contact Dermatitis 1984:11:279-282.

Munksgaard EC. Permeability of protective gloves to (di)methacrylates in resinous dental materials. 25.

Scand J Dent Res 1992:100:189-192.

Andreasson H, Boman A, Johnsson S, Karlsson S, Barregard L. On permeability of methyl 26.

methacrylate, 2-hydroxyethyl methacrylate and triethyleneglycol dimethacrylate through protective

gloves in dentistry. Eur J Oral Sci 2003:111:529-535.

Fartasch M, Taeger D, Broding HC, Schoneweis S, Gellert B, Pohrt U, 27. et al. Evidence of increased

skin irritation after wet work: impact of water exposure and occlusion. Contact Dermatitis

2012:67:217-228.

Ramsing DW, Agner T. Effect of glove occlusion on human skin (II). Long-term experimental expo-28.

sure. Contact Dermatitis 1996:34:258-262.

Long CC, Finlay AY. The finger-tip unit- a new practical measure. 29. Clin Exp Dermatol

1991:16:444-447.

Gupta G, Mallefet P, Kress DW, Sergeant A. Adherence to topical dermatological therapy: lessons 30.

from oral drug treatment. Br J Dermatol 2009:161:221-227.

Krejci-Manwaring J, McCarty MA, Camacho F, Carroll CL, Johnson K, Manuel J, 31. et al. Adherence

with topical treatment is poor compared with adherence with oral agents: implications for effective

clinical use of topical agents. J Am Acad Dermatol 2006:54:S235-6.

10chapter

236

Hix E, Gustafson CJ, O’Neill JL, Huang K, Sandoval LF, Harrison J, 32. et al. Adherence to a five day

treatment course of topical fluocinonide 0.1% cream in atopic dermatitis. Dermatol Online J

2013:19:20029.

Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic 33.

eczema. Br J Dermatol 2000:142:931-936.

Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. 34.

Health Technol Assess 2000:4:1-191.

van Velsen SG, Haeck IM, Bruijnzeel-Koomen CA. Percutaneous absorption of potent topical 35.

corticosteroids in patients with severe atopic dermatitis. J Am Acad Dermatol 2010:63:911-913.

Terra JB, Potze WJ, Jonkman MF. Whole body application of a potent topical corticosteroid for 36.

bullous pemphigoid. J Eur Acad Dermatol Venereol 2014:28:712-718.

Miest RY, Yiannias JA, Chang YH, Singh N. Diagnosis and prevalence of lanolin allergy. 37.

Dermatitis 2013:24:119-123.

Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. 38. Dermatitis 2008:19:38-42.

Green CM, Holden CR, Gawkrodger DJ. Contact allergy to topical medicaments becomes more 39.

common with advancing age: an age-stratified study. Contact Dermatitis 2007:56:229-231.

Baeck M, Chemelle JA, Terreux R, Drieghe J, Goossens A. Delayed hypersensitivity to 40.

corticosteroids in a series of 315 patients: clinical data and patch test results. Contact Dermatitis

2009:61:163-175.

Baeck M, Chemelle JA, Goossens A, Nicolas JF, Terreux R. Corticosteroid cross-reactivity: clinical 41.

and molecular modelling tools. Allergy 2011:66:1367-1374.

Baeck M, Goossens A. Immediate and delayed allergic hypersensitivity to corticosteroids: practical 42.

guidelines. Contact Dermatitis 2012:66:38-45.

Baeck M, Goossens A. New insights about delayed allergic hypersensitivity to corticosteroids. 43.

G Ital Dermatol Venereol 2012:147:65-69.

Katsarou A, Makris M, Papagiannaki K, Lagogianni E, Tagka A, Kalogeromitros D. Tacrolimus 0.1% 44.

vs mometasone furoate topical treatment in allergic contact hand eczema: a prospective

randomized clinical study. Eur J Dermatol 2012:22:192-196.

Schnopp C, Remling R, Möhrenschlager M, Weigl L, Ring J, Abeck D. Topical tacrolimus (FK506) 45.

and mometasone furoate in treatment of dyshidrotic palmar eczema: a randomized,

observer-blinded trial. J Am Acad Dermatol 2002:46:73-77.

Waernulf L, Moberg C, Henriksson EW, Evengard B, Nyberg F. Patients’ views on care and 46.

treatment after phototherapy for psoriasis and atopic eczema including a gender perspective.

J Dermatolog Treat 2008:19:233-240.

van Coevorden AM, Coenraads PJ, Stant AD, Duizendstraal A. Thuisbehandeling van handeczeem 47.

met PUVA (THP). 2002:VAZ/CVZ 99252.

10chapter

237

van Coevorden AM, Kamphof WG, van Sonderen E, Bruynzeel DP, Coenraads PJ. Comparison of 48.

oral psoralen-UV-A with a portable tanning unit at home vs hospital-administered bath

psoralen-UV-A in patients with chronic hand eczema: an open-label randomized controlled trial of

efficacy. Arch Dermatol 2004:140:1463-1466.

Ruzicka T, Larsen FG, Galewicz D, Horvath A, Coenraads PJ, Thestrup-Pedersen K, 49. et al. Oral

alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard

therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial.

Arch Dermatol 2004:140:1453-1459.

Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, 50. 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.

Bissonnette R, Worm M, Gerlach B, Guenther L, Cambazard F, Ruzicka T, 51. et al. Successful

retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol

2010:162:420-426.

Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema - 52.

a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007:21:606-619.

van der Schaft J, Politiek K, Schuttelaar MLA, de Bruin-Weller MS. Drug survival for cyclosporin A in 53.

a long-term daily practice cohort of adult patients with atopic dermatitis. manuscript in

preparation.

Egan CA, Rallis TM, Meadows KP, Krueger GG. Low-dose oral methotrexate treatment for 54.

recalcitrant palmoplantar pompholyx. J Am Acad Dermatol 1999:40:612-614.

Agarwal US, Besarwal RK. Topical clobetasol propionate 0.05% cream alone and in combination 55.

with azathioprine in patients with chronic hand eczema: an observer blinded randomized

comparative trial. Indian J Dermatol Venereol Leprol 2013:79:101-103.

Scerri L. Azathioprine in dermatological practice. An overview with special emphasis on its use in 56.

non-bullous inflammatory dermatoses. Adv Exp Med Biol 1999:455:343-348.

Neuber K, Schwartz I, Itschert G, Dieck AT. Treatment of atopic eczema with oral mycophenolate 57.

mofetil. Br J Dermatol 2000:143:385-391.

Haeck IM, Knol MJ, Ten Berge O, van Velsen SG, de Bruin-Weller MS, Bruijnzeel-Koomen CA. 58.

Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult

patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol

2011:64:1074-1084.

Diepgen TL, Andersen KE, Chosidow O, Coenraads PJ, Elsner P, English J, 59. et al. Guidelines for

diagnosis, prevention and treatment of hand eczema. J Deutsche Dermatol Gesellschaft - ahead of

printing.

10chapter

238

Diepgen TL, Andersen KE, Brandao FM, Bruze M, Bruynzeel DP, Frosch P, 60. et al. Hand eczema

classification: a cross-sectional, multicentre study of the aetiology and morphology of hand

eczema. Br J Dermatol 2009:160:353-358.

Lynde C, Cambazard F, Ruzicka T, Sebastian M, Brown TC, Maares J. Extended treatment with oral 61.

alitretinoin for patients with chronic hand eczema not fully responding to initial treatment.

Clin Exp Dermatol 2012:37:712-717.

Johansen JD, Hald M, Andersen BL, Laurberg G, Danielsen A, Avnstorp C, 62. et al. Classification of

hand eczema: clinical and aetiological types. Based on the guideline of the Danish Contact

Dermatitis Group. Contact Dermatitis 2011:65:13-21.

Molin S, Diepgen TL, Ruzicka T, Prinz JC. Diagnosing chronic hand eczema by an algorithm: a tool 63.

for classification in clinical practice. Clin Exp Dermatol 2011:36:595-601.

Weistenhofer W, Baumeister T, Drexler H, Kutting B. An overview of skin scores used for 64.

quantifying hand eczema: a critical update according to the criteria of evidence-based medicine.

Br J Dermatol 2010:162:239-250.

Tugwell P, Boers M, Brooks P, Simon L, Strand V, Idzerda L. OMERACT: an international initiative to 65.

improve outcome measurement in rheumatology. Trials 2007:8:38.

Schmitt J, Williams H, HOME Development Group. Harmonising Outcome Measures for Eczema 66.

(HOME). Report from the First International Consensus Meeting (HOME 1), 24 July 2010, Munich,

Germany. Br J Dermatol 2010:163:1166-1168.

Agner T, Jungersted JM, Coenraads PJ, Diepgen T. Comparison of four methods for assessment of 67.

severity of hand eczema. Contact Dermatitis 2013:69:107-111.

Ofenloch RF, Weisshaar E, Dumke AK, Molin S, Diepgen TL, Apfelbacher C. The Quality of Life in 68.

Hand Eczema Questionnaire (QOLHEQ): validation of the German version of a new disease-

specific measure of quality of life for patients with hand eczema. Br J Dermatol 2014:17:304-312.

Schuttelaar ML, Vermeulen KM, Coenraads PJ. Costs and cost-effectiveness analysis of treatment 69.

in children with eczema by nurse practitioner vs. dermatologist: results of a randomized, controlled

trial and a review of international costs. Br J Dermatol 2011:165:600-611.

Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 Statement: updated 70.

guidelines for reporting parallel group randomised trials. Trials 2010:11:32-6215-11-32.

Williams HC. Cars, CONSORT 2010, and clinical practice. 71. Trials 2010:11:33-6215-11-33.

von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, 72. et al. The

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement:

guidelines for reporting observational studies. Lancet 2007:370:1453-1457.

Thyssen JP, Ross-Hansen K, Johansen JD, Zachariae C, Carlsen BC, Linneberg A, 73. et al. Filaggrin

loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the

hands: results from a cross-sectional population study. Br J Dermatol 2012:166:46-53.

10chapter

239

Thyssen JP, Johansen JD, Zachariae C, Menné T, Linneberg A. Xerosis is associated with atopic 74.

dermatitis, hand eczema and contact sensitization independent of filaggrin gene mutations.

Acta Derm Venereol 2013:93:406-410.

Molin S, Vollmer S, Weiss EH, Ruzicka T, Prinz JC. Filaggrin mutations may confer susceptibility to 75.

chronic hand eczema characterized by combined allergic and irritant contact dermatitis.

Br J Dermatol 2009:161:801-807.

Thyssen JP, Carlsen BC, Menné T, Linneberg A, Nielsen NH, Meldgaard M, 76. et al. Filaggrin null

mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis:

results from a general population study. Br J Dermatol 2010:163:115-120.

Hersle K, Mobacken H. Hyperkeratotic dermatitis of the palms. 77. Br J Dermatol 1982:107:195-201.

10chapter

240