Optiuni de tratament in eczema.pdf

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ORIGINAL ARTICLE

Redefining treatment options in chronic hand eczema (CHE)

Robert Bissonnette, Thomas L. Diepgen, Peter Elsner, John English, Robin Graham-Brown,

Bernhard Homey, Thomas Luger,,* Charles Lynde, Jurgen Maares, Howard I. Maibach

Innovaderm Research, Montreal, QC, CanadaDepartment of Social Medicine, Occupational and Environmental Dermatology, University Hospital of Heidelberg, Heidelberg,

GermanyFriedrich Schiller University, Jena, GermanyQueens Medical Centre, Nottingham, UKUniversity Hospitals of Leicester, Leicester, UKHeinrich-Heine-University, Dusseldorf, GermanyUniversity Clinics Munster, Munster, GermanyLynderm Research, Markham, ON, CanadaBasilea Pharmaceutica International Ltd, Basel, SwitzerlandUniversity of California, San Francisco, CA, USA

*Correspondence: T Luger. E-mail:[email protected]

Introduction

Professor T. Luger

Chronic hand eczema (CHE) is not a uniform disease. Differ-

ences in aetiology, morphology and severity make accurate diag-

nosis difficult, further hampered by the lack of a systematic

classification system. Until now, patients with severe CHE have

had few treatment options available to them if topical cortico-

steroids have failed to improve their situation. This supplement,

based on a standalone meeting that took place in Paris, is acollection of presentations given by an internationally renowned

panel of experts in CHE, covering every aspect of the disease

and its treatment. It also captures questions raised by the audi-

ence during that meeting and makes this extensive summary the

most comprehensive and up-to-date synopsis of current thinking

within CHE.

The first part looks at current understanding of the disease,

difficulties in diagnosis and the need for a systematic classification

system to improve patient outcomes. This is followed by a discus-

sion on the role of the skin barrier and how, by using the full range

of investigative methods available to dermatologists and compre-

hensively documenting skin barrier function, the aetiology of CHE

can be better understood. Then two sections follow on the impactof CHE on both society and the patient to capture on one hand

the social, occupational and economic burden of CHE, and on the

other hand, what it means for the patient to live on a daily basis

with such a chronic and relapsing disease. The second part of the

supplement presents the benefits and limitations of current treat-

ment options, including topical and systemic therapies. It reflects

current treatment paradigms, and the clinical evidence supporting

them. The pharmacology of alitretinoin an endogenous vitamin

A derivative and, an emerging systemic treatment for the manage-

ment of severe CHE is introduced in the following section. This

is followed by a discussion on the proposed mode of action of

alitretinoin and its interference at different steps in the immune

and inflammation processes within the skin. Clinical data are then

presented from the Benefit of Alitretinoin in Chronic Hand

Eczema (BACH) study, the largest controlled trial in CHE to date,

and a retreatment study demonstrating that patients who previ-

ously achieved clear or almost clear hands during the BACH study

also responded to a second course of treatment, allowing for inter-

mittent long-term treatment of this chronic disease. Combined

safety data from the large alitretinoin phase III clinical trials com-plete this section. The third part of the supplement concludes by

assessing methods of advancing CHE management in clinical prac-

tice using evidence-based medicine (EBM), and the development

of much-needed treatment guidelines. It also includes a short sec-

tion aimed at providing answers to some of the commonly asked

questions on alitretinoin usage in a daily clinical practice.

Understanding CHE and its impacton society and the individualpatient

Understanding the disease, diagnosisand classification

Professor T. L. Diepgen

Hand eczema prevalence, epidemiology and

aetiology

Hand eczema (HE) is the most common skin disorder affecting

the hands. In a substantial number of patients, HE can develop

into a chronic condition, with disease remaining active even after

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DOI: 10.1111/j.1468-3083.2010.03615.x JEADV


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contact with potentially damaging allergens andor irritants has

been avoided.1 CHE has been defined as either a long-lasting,

relapsing course of HE, or HE unresponsive to standard treatment

with emollients and topical corticosteroids. It is estimated that 5

7% of HE patients have severe CHE, and 24% are unresponsive

to standard treatment.2

Hand eczema is not a uniform disease and varies because of dif-

ferences in aetiology, morphology and severity. About 50% of HE

patients seek some form of dermatological treatment and 5% of

HE patients are on sick leave at any given time.2 Prevalence rates

account for up to 30% of HE amongst specific, high-risk, occupa-

tional groups involved in wet work, or exposed to irritant andor

allergic substances (such as hairdressers, cooks, cleaners, healthcare

workers, etc.).3 Some studies have shown a higher incidence of HE

in female patients, which is most likely because of environmental

factors.2 Atopy is also a risk factor for HE.4,5 It has been estimated

that 7080% of childhood eczema is because of an inherited aller-

gic susceptibility, and amongst those with childhood eczema, athreefold increase in the risk of HE has been observed.5 Exposure

to environmental factors, such as skin allergens or irritants, and

endogenous factors, such as atopy, play interrelated roles in the

aetiology of HE. It is rarely possible to identify all causative factors

and remove them entirely.2,6,7

Hand eczema has a poor long-term prognosis. In a 15-year fol-

low-up study, patients diagnosed with HE were questioned con-

cerning the persistence and course of their disease.8 Of the 868

patients who answered the questionnaire, 66% reported periods of

HE during the preceding 15 years, 44% reported symptoms during

the previous 12 months, 12% reported continuous eczema and 3%

of those who were gainfully employed during the original study in1983, reported a change in occupation because of their HE (15 of

these reported improvement after the job change). The study

found that risk factors associated with a poor long-term prognosis

included the extent of eczema involvement at initial examination,

a history of childhood eczema and onset of HE prior to the age of

20.8 All of these individual factors significantly influenced the total

time suffering from HE during the previous 15 years and the

occurrence of HE in the immediately preceding year. Patients with

all three risk factors had twice the chance of still having HE after

15 years compared with patients with none of the risk factors.8

Classification and morphology

There is currently no universally accepted classification for HE,and most published classifications invoke a combination of aetio-

logical factors (irritant, allergic and atopic disease) and morpho-

logical features such as hyperkeratotic or vesicular (dyshidrotic,

pompholyx) eczema. No existing system completely accounts for

the existence of hybrids and combinations of the various morpho-

logical categories, or overcomes the inability to determine aetiol-

ogy in a high proportion of cases.

Agreement on a classification system for the subtypes of HE will

be an important step in improving outcomes for patients suffering

from this debilitating condition by facilitating earlier and more

accurate diagnoses, and hence, more effectively targeted therapy.

Diagnosis

Given these limitations, accurate diagnosis of the disease is chal-

lenging and should be initiated by taking a full and careful medical

history. Patients should be questioned about their previous HE

history, particularly that relating to the type of lesions and the

time courses of both flares and remitting periods. The morphology

and location of the lesions must be examined as this will help

exclude differential diagnosis with psoriasis, and infections or

other causes must be excluded. Patch tests, guided by occupational

and leisure time history, should be considered as a mandatory

step. Positive patch-test findings require specialist interpretation

with regards to relevance to current disease activity of CHE.

Chronic hand eczema

In a substantial number of HE patients, the disease develops into achronic condition even when an initial causative agent is avoided.2

Particularly in the case of occupational dermatoses, allergic and

irritant contact dermatitis usually appears to precede the develop-

ment of a more chronic condition. It is possible that the inflamma-

tory changes in the skin increase the likelihood of acquiring a

secondary allergy the second stage in a long series of events. Sen-

sitization may possibly be allayed by offering preventative measures

at the point where irritant contact dermatitis starts, thereby pre-

venting the sequelae which may follow. Clinical signs and symp-

toms of CHE comprise classic features of eczema localized to the

hands, including erythema, oedema, hyperkeratosis, scaling, liche-

nification, vesiculation

blistering, fissures, pruritus and pain.

912

The role of the barrier function in CHE

Professor H. I. Maibach

Impaired skin barrier function is a key factor in eczema. Skin bar-

rier function can be impaired by a genetic predisposition to pro-

duce increased levels of stratum corneum chymotryptic enzyme, a

protease enzyme that causes premature breakdown of corneodes-

mosomes, leading to impairment of the epidermal barrier. The

addition of environmental interactions or long-term application of

topical corticosteroids can further increase production of stratumcorneum chymotryptic enzyme and impair epidermal barrier

function. The epidermal barrier can also be damaged by exoge-

nous proteases from house dust mites and Staphylococcus aureus.

Defective skin barrier function increases the risk of penetration of

irritants and allergens through the skin. This initiates immunologi-

cal reactions and inflammation.

It is possible that all of the disease subtypes loosely called hand

eczema syndrome have differently impaired skin barrier functions,

and, given the lack of agreement on their disease morphology, we

2010 The AuthorsJEADV 2010,24 (Suppl. 3), 120 Journal compilation 2010 European Academy of Dermatology and Venereology

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need to fully understand all of the skin barrier elements that are

influential in the eczematous hand as this could have profound

therapeutic ramifications. Non-invasive bioengineering methods,

including the measurement of transepidermal water loss (TEWL)

and water capacitance, have been commonly used to evaluate skin

barrier function. Studies also suggest that ionic signals such as cal-

cium and potassium play an important role in the homeostatic

mechanism of the epidermal barrier function. Delineating changes

in these skin barrier functions may offer not only more robust and

early signals of normalization, but may aid clearer separation of

the aetiological processes than morphology alone and allow differ-

entiating factors in the various forms of HE to be pinpointed.

Only by serially documenting skin barrier function in CHE may

we 1 day hope to fully understand this complex condition.

A brief summary of these methods is provided below.

1 Transepidermal Water Loss In the 1960s Malten and

Spruit13 pioneered the technique of measuring water trans-

port through the skin. Many publications have beendevoted to TEWL; however, other areas of barrier function

have consequently been neglected.

2 Molecules involved in regulating barrier functions:

Carbon dioxide14,15 The transport of CO2 has been

shown to vary in different types of HE

Chlorides16 Transepidermal chloride flux through

hydrated skin appears to be a viable method for determin-

ing stratum corneum function in vivo

Oxygen17

Potassium18 It has been found that damage to the epi-

dermal water barrier does not necessarily result in damage

to the epidermal electrolyte barrier Calcium is thought to play various roles in the formation

of the stratum corneum barrier and abnormal calcium

distribution is observed in psoriatic epidermis and also in

atopic eczema. Assessing its transepidermal movement in

different types of HE could therefore provide useful differ-

entiating data.

3 Keratin metrics. The stratum corneum is removed via tape-

stripping and is measured both functionally and quantita-

tively.19 This method provides quantification of the sodium

hydroxide soluble protein fraction via a commercially available

protein assay. The amount of stratum corneum removed is of

relevance in establishing the concentration profile of chemicals

within this layer and hence the uptake of therapeutic drugs.4 Messenger RNA (mRNA) in stripped skin when combined

with a ribonuclease protection assay allows the quantifica-

tion of molecular changes.20 Studies have shown that multi-

ple cytokine mRNA levels can be defined in these RNA

samples assessing not only the cytokine gene profiles, but

also potentially, the severity of common irritant vs. allergic

skin reactions. Measurements of cytokine mRNA may pro-

vide a method to distinguish irritant contact and allergic

contact dermatitis.

Appropriately combining these simple, non-invasive, techniques

should allow us to gain new insights into the various morphologi-

es that have been grouped together under the terminology of HE.

Unanswered questions

One enigma occurs in cases of hyperkeratotic psoriasiform

eczema. This presents as marginated hyperkeratosis on the hands

(with or without erythema) with psoriasiform hyperkeratosis of

the elbows and knees sometimes extending down the forearms.

Another variant has fissuring of the fingertips. However, histology

shows this condition to be spongiosis or eczema not psoriasis.

Many patients with severe psoriasiform or hyperkeratotic eczema

will only respond to occlusive therapy, although penetration data

suggests that it should not be required.21 Further investigations

with the currently available technologies may help to resolve these

issues.

Further areas of investigationOne area of investigation of barrier function is to compare how

the palm of the hand compares in reactivity with the dorsal hand

and the forearm when responding to irritants. Significant damage

can be performed to the palm and the dorsum of the hand with

very little change in morphology. Often, the morphology is so

hidden when the skin is irritated that a number of different tools

are needed to observe the damage that has been performed. One

extremely discriminating tool in very low grade irritancy dermati-

tis is squamometry where an adhesive disc is used as a harvesting

method for the superficial desquamating layer of the stratum cor-

neum. The disc can then be rated by visual examination, weight-

ing, optical measurement (with or without staining), imageanalysis, protein assay or morphology.22 Novel approaches to

investigate the structure and barrier function of the skin include

atomic force microscopy of tape stripped skin and 5D intravital

tomography.23,24

Additional mechanistic and methodological details can be

found in Karanet al.25

Impact of CHE on society and the

patient

Dr J. English

In addition to the direct medical consequences of the disease,

CHE causes significant problems and burdens to patients and to

society.

Psychosocial burden of CHE

There is generally a social stigma associated with any visible skin

disease, which can be a significant burden for the patient. CHE is

localized on a highly visible area of the body the hands which


Redefining treatment options in chronic hand eczema (CHE) 3


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are important organs of communication and expression. Any

impairment in function and form may result in major psychoso-

cial problems such as anxiety, low self-esteem, and social phobia.

Severe CHE is associated with a significant lowering of quality of

life comparable with that of generalized eczema or psoriasis. A lack

of understanding of the disease in the general population contrib-

utes to the problem almost 50% of HE patients surveyed said

they suspected other people thought the disease was contagiouswhilst 81% said that HE interferes with their daily life.26 The table

below shows some of the psychosocial consequences of CHE as

they were assessed in a population in 1990, and at a 15-year fol-

low-up study in the same population (Table 1). The results

showed a variable and poor long-term prognosis in this popula-

tion. The effects of these and other disturbances can be far reach-

ing. Patients may avoid going on holiday because of the

difficulties of preparation and adaptation in a new location or

because of embarrassment exposing their body in swimwear. Hob-

bies may be abandoned because of allergic reactions to the tools

required.

Occupational burden of CHE

Chronic hand eczema has also been shown to be a major cause of

morbidity and lost earnings with symptoms such as itching, blis-

ters and painful fissures limiting patients abilities to carry out

some occupations. A random sample of 20 000 people in

Gothenburg, Sweden, were sent a questionnaire asking about HE.

Eighty-three percentage of those contacted responded and, of

these people, 1238 had a confirmed diagnosis of HE.26 21.4% of

the HE sufferers reported at least one period of sick leave from

work lasting a minimum of 7 days, whilst 4.4% reported more

than five separate sick leave periods (of minimum 7 days dura-

tion).26 The mean total sick leave time during the previous year

was 4.0 weeks.Other studies have shown similar results, although conducted

on a much shorter time scale. A postal survey of 758 Danish HE

patients showed that 57% of the 579 responders to this item in the

questionnaire reported sick leave because of occupational HE dur-

ing the past 12 months. Of these, prolonged sick leave, defined as

more than 5 weeks per year, was reported by 19.9%.27

Hand eczema can also force patients to change occupation. The

Swedish study found that up to 8% of HE patients had been

forced to change jobs because of their disease.26 Changes were

more frequent in service work, production and medicalnursing

careers, and the rate of change of occupation was as high as 18%

in some professions.

Economic burden of CHE

The impact of any disease on society is felt through economic loss,

both direct (from the cost to healthcare authorities of drug treat-

ments or hospitalphysician visits) and indirect (absenteeism from

work because of illness).

The economic impact of HE is considerable. Direct medical

costs including treatment, medication and visits to the GP alone

have been estimated at 11 billion per year in the EU.2 These fig-

ures do not include direct non-medical costs such as travel, infor-

mal care, time and out-of-pocket costs, or the indirect non-

medical costs such as loss of productivity because of reduced per-

formance at work or sick leave.28

A recent study examined the direct and indirect cost of illness

in work-related CHE in Germany using data from 151 patientswith occupational skin diseases.29 Information on resource utiliza-

tion (e.g. drug use, rehabilitation, diagnostic tests, physician visits,

etc.) was recorded and unit costs for each type of resource utiliza-

tion determined and multiplied. Indirect costs were calculated

according to the human-capital-method (days lost from work

multiplied by mean gross income estimated by the German Statu-

tory Pension Fund for 2007). Analyses were performed for the

total group and by disease severity. The most frequent types of

costs identified were dermatologist visits, application of topical

corticosteroids and lost work days. Other resources used included

frequent PUVA therapy and inpatient rehabilitation. Indirect costs

were by far the largest proportion constituting 70% of the totalbill. Total annual costs of work-related CHE amounted to 8,799

per patient comparable with the costs incurred for severe psoria-

sis or atopic eczema.

As indirect costs are the critical cost drivers for CHE, a reduc-

tion in days lost from work and therefore the costs associated with

this absence, would provide the most potent reduction in costs to

society. An effective therapy should therefore provide a significant

cost saving to healthcare authorities and society in general.

Impact of CHE on the patient

The impact of severe CHE on the individual patient cannot be

underestimated as its occupational, domestic, social and psycho-

logical impact is considerable. The occupational and psychosocialimpacts have been discussed in the previous section.

Domestic impact of CHE

Lack of sleep30 because of pain and itching adds to the cumulative

stresses of CHE, and together these can cause frustration amid

feelings that a patient is unable to cope with everyday life. This

can lead to a straining of interpersonal relationships. Adjustments

are also required in all aspects of home-life when patients begin to

experience the debilitating symptoms of CHE.

Table 1 Psychosocial consequences of hand eczema

Type of disturbance

Percentage of

patients 199022Percentage of

patients 200527

Handicap in leisure activities 50 72

Change in daily activities 32 56

Sleep disturbance 34 36

Mood disturbance 39 46

Avoided contact 33

Gave up hobbies 18 16




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All of these factors, combined with a potentially increased fiscal

burden because of private medical bills and specialist products,

place an enormous strain on the CHE patient. Faced with a condi-

tion that can last for decades and physicians who are unable to

offer long-term solutions, burden of disease is a truly meaningful

concept.

Current and emerging treatment strategies in CHE

Benefits and limitations of current

treatment strategies

Dr R. Graham-Brown

Chronic hand eczema is a disease with a multifactorial aetiology

and clinical presentation does not always correspond to disease

phenotype. Consequently, treatment objectives are universal, irre-

spective of phenotype, and include elimination or reduction ofexposure to causative factors, symptom control, and reduction of

frequency and severity of flares.

Patients with CHE require long-term management and therapy

is usually delivered in escalating steps.

1. Education and non-pharmacological methods

Initial treatment steps involve education regarding skin protection

measures and lifestyle changes to minimize exposure to allergens

or irritants. Hands may be protected with gloves to avoid exposure

to trigger factors, although the gloves themselves can sometimes

aggravate the condition. Emollient creams are standard therapy

for all patients and should be used irrespective of other treatments.

They prevent the skin from becoming dry, provide basic barrier

protection from irritants, help prevent itch and reduce the fre-

quency of flare-ups.

2. Topical therapies

Topical corticosteroids: The initial medical intervention for CHE is

usually topical corticosteroids. They are fast acting and are effec-

tive in the short-term for controlling the disease in many patients;

however, their suitability is limited by rebound flare-ups, tachy-

phylaxis and lack of efficacy in severely affected patients.31 Long-

term corticosteroid usage can also cause skin atrophy and may

contribute to further weakening of the skin barrier. This is particu-

larly true for potent topical corticosteroids.Topical immunomodulators: The topical immunomodulators

(pimecrolimus and tacrolimus) are not licensed for, but have been

investigated in, the treatment of mild to moderate CHE. A ran-

domized, study in 294 patients with mild-to-moderate CHE com-

pared a twice-daily application of pimecrolimus cream 1% (with

overnight occlusion) with a vehicle control.32 By the final visit on

day 22, there was only a trend (with no statistical significance),

towards greater clearance in patients who received pimecrolimus

than for those treated with vehicle cream.

Photochemotherapy (PUVA): Photochemotherapy can be useful

in combination with other topical or systemic therapies but has a

considerable impact on a patients lifestyle and is not widely avail-

able.33 Of the controlled studies published, few have shown

evidence of more than limited efficacy in CHE, with no informa-

tion available on the magnitude of response to treatment. Phot-

ochemotherapy, however, is an inconvenient treatment, requiring

numerous office or hospital visits.

Approximately 24% of patients with severe CHE are refractory

to topical treatment, and current treatment options for these

patients are clearly limited.2

3. Systemic therapies

The off-licence use of systemic treatments has been reported, but

there is a lack of clinical evidence supporting their long-term effi-

cacy and safety in this indication.

Oral corticosteroids: Whilst oral corticosteroids may be useful

for the immediate treatment of an acute flare, their long-term useis generally not appropriate as they have significant side effects

and long-term toxicities.

Oral retinoids:Retinoids have been used successfully to treat dif-

ferent dermatological disorders since the early 1980s. While cur-

rent retinoids have been proven to be effective for the treatment of

psoriasis, acne and some genodermatoses, there is little reported

evidence of the use of oral retinoids in CHE. A small exploratory

study of acitretin (40 mg daily) in patients with hyperkeratotic

eczema (n= 14 receiving active treatment) showed a decrease in

some symptoms of up to 50% at week 4 with no further improve-

ment at week 8.34 However, it should be noted that the study did

not explicitly define the patient population in terms of eitherseverity or disease responsiveness.

Immunosuppressants:A study investigated the efficacy of ciclo-

sporin (3 mgkgday) vs. betamethasone (0.05% cream) in 41

patients with CHE who had an inadequate response to topical cor-

ticosteroids.35 The total disease activity score decreased by 57% of

baseline in the ciclosporin group and 58% in the betamethasone

group. There was no difference in response between the treat-

ments, and 50% of patients in both groups relapsed after treat-

ment was stopped (during the 24-week relapse-observation

period).35 Ciclosporin is associated with kidney toxicity and

hypertension, and patients must be carefully monitored. Azathio-

prine has been shown to be effective in atopic eczema,36 and whilst

atopic eczema is a recognized risk factor for CHE, no specific stud-ies in CHE have been performed.

A recent literature review of the current available treatment

options in CHE (developed as part of a long-term project to

improve standards of design and reporting in HE trials) examined

published trials from 1997 to 2003.37 This review described the

study designs and commented on the quality of reporting of the

trials. A total of 90 studies reported in 87 papers dealt with 11 dif-

ferent classes of interventions. Around 80% of the studies dealt

with just four interventions: ultraviolet light, topical corticosteroids,




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radiation and systemic immunosuppressants. Of the 90 studies,

44 were case series, 15 were non-randomized controlled trials,

and the remaining 31 were randomized controlled trials (RCTs).

Of these 31 RCTs, 16 were parallel (one with cross-over design)

and 15 self-controlled. Only 11 of the RCTs adequately reported

eligibility criteria. The randomization method was described in

10, and there was adequate concealment of allocation in eight.

Masking the treatment allocation from both the study assessors

and patients was performed in 11 RCTs, and intention-to-treat

analysis was reported in four. Only 13 RCTs were 4 months or

longer in duration. No study reported a rationale for the sample

size, and in only one study had the outcome variable been vali-

dated. The authors concluded that the strength of the clinical-

trial evidence for the multitude of currently available options for

the treatment of CHE was limited, and not adequate to guide

clinical practice. Future trials in HE, they said, needed to be ran-

domized, with a parallel group or self-controlled design, and use

validated and clinically relevant outcome measures.Given the limitations of current treatments and the lack of con-

sensus between prescribers, there is a clear, unmet need, for effec-

tive long-term management of severe CHE that is unresponsive to

potent topical corticosteroids.

Toctino

(oral alitretinoin) a new

treatment for severe CHE: discovery,

pharmacology and pharmacokinetics

Dr J. Maares

Retinoids are vitamin A derivatives that can be either endogenous

physiological or synthetic and they display key regulatory func-

tions in epidermal growth and differentiation. Treatment with ret-

inoids is associated with specific class effects such as skin reactions

(mucocutaneous effects, dry skin, cheilitis), metabolic effects (ele-

vations in triglycerides and cholesterol), and hepatic effects (eleva-

tions in transaminases and bilirubin).

Isotretinoin, etretinate, acitretin and alitretinoin all belong to

the class of retinoids. However, they differ from one another

because of their pharmacological properties.

Isotretinoin is a naturally occurring retinoid found in the body

in small quantities. It was approved for use in severe acne in 1982and is still considered to be the most effective therapy available in

this indication.

Etretinate is a synthetic retinoid that was launched in 1986 and

was used primarily for the treatment of severe recalcitrant psoriasis

before being superseded by acitretin.

Alitretinoin (9-cis-retinoic acid) is an isomer of isotretinoin

(13-cis-retinoic acid). It is an endogenous physiological retinoid

and is the only drug that has been specifically developed for the

indication of CHE.

There are two structurally distinct families of nuclear receptors

associated with the retinoids retinoic acid receptors (RARs) and

retinoid X receptors (RXRs).

Each of these families in turn contains three distinct receptors,

termed alpha, beta and gamma, with more isoforms belonging to

each subtype.38 The existence of numerous retinoid receptor iso-

forms may explain the complexity and pleiotropic activity of reti-

noids.39 RARs bind both all-trans- and 9-cis-retinoic acid, but only

9-cis-retinoic acid binds to RXRs.

Alitretinoin has been described as a panagonist of retinoid

receptors because it binds to RAR receptors and RXR receptors.

Binding to and activation of the various retinoid receptors might

be responsible for certain biological effects of alitretinoin, however,

no precise link has been shown between patterns of receptor bind-

ing and therapeutic activity in CHE. The exact mechanism of

action of alitretinoin in the treatment of CHE is currently

unknown.

Although structurally related to isotretinoin, alitretinoin is asso-ciated with significantly less suppression of human sebum secre-

tion.40 This finding may account for the lack of efficacy

demonstrated by alitretinoin in a small acne trial, and suggests a

possible basis for the low incidence of mucocutaneous side effects

seen in the alitretinoin clinical development programme.40,41

Early dose-finding studies assessed single ascending and multi-

ple oral doses in healthy volunteers and oncology patients of up to

150 mgm2.42,43 Pharmacokinetics were found to be linear over

the doses studied. Single-dose peak plasma concentrations were

achieved within 34 h on average, the half-life was 1.32.4 h and

the drug was eliminated within 24 h. The drug tolerability was

consistent with other retinoids as were the adverse events (AEs),including headache and diarrhoea, which were dose limiting at the

highest doses. Data from 32 CHE patients who received alitretino-

in 10 mg or 30 mg for 24 weeks showed that the pharmacokinet-

ics of the drug were linear and there was no evidence of time-

dependent pharmacokinetics or accumulation of alitretinoin.44

Drugdrug interaction studies of alitretinoin with inhibitors or

substrates of CYP 3A4 were conducted. When co-administered

with ketoconazole, a strong inhibitor of CYP 3A4, alitretinoin

AUC increased by 40% and Cmax by 60%. However, alitretinoin

did not affect the pharmacokinetics of ketoconazole or ciclosporin

A. A slight reduction of simvastatin plasma levels (AUC decreased

by 16% and Cmaxby 23%) was observed when co-administered

with alitretinoin, although simvastatin and ciclosporin A did notaffect the pharmacokinetics of alitretinoin.45

Significant increases (P < 0.001) in the mean Cmaxand mean

AUC have been observed when alitretinoin is given with food,

with systemic exposure enhanced by a factor of four, and variabil-

ity of exposure markedly decreased.46 Alitretinoin should therefore

always be taken with a meal. No influence of body weight on ali-

tretinoin exposure was noted in pharmacology trials. Correspond-

ingly, no correlation between body weight and clinical response

was noted in clinical trials.




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Like all retinoids, alitretinoin is a strong teratogen and strict

pregnancy prevention measures must be observed before, during

and after treatment. Alitretinoin has a shorter half-life (mean t210 h) than acitretin (meant3996 h). This is particularly rele-

vant for females of childbearing potential as contraception is

required for 1-month post-treatment with alitretinoin compared

with 3 years for acitretin.

Alitretinoin has no clinically relevant pharmacokinetic interac-

tions with the commonly prescribed combined oral contraceptive

(COC) ethinyl estradiolnorgestimate, suggesting COCs are an

appropriate primary method of contraception. For male patients,

the amount of alitretinoin (or its metabolite) transferred by semi-

nal fluid to female partners is negligible, and therefore barrier con-

traception is not required during treatment.

Toctino (oral alitretinoin) explaining

the anti-inflammatory effect

Professor B. Homey

Chronic hand eczema has been shown to be caused by exposure

to either irritant or allergicatopic trigger factors. Although the

clinical features of CHE are well defined, the underlying patho-

physiological mechanisms are still not fully understood. In con-

trast to direct tissue damage induced by chemical irritants or

mechanical injury, which subsequently leads to local inflamma-

tion, the induction of allergic responses by haptens or allergens

activates not only the epidermal compartment but also the

immune system, characterized by the induction of antigen-specific

effector and memory T cells. The recruitment of distinct leucocyte

subsets to sites of inflammation has been shown to be critically

regulated by chemokines and their receptors.

During contact irritancy, structural cells as well as resident cells

of the skin immune system are primarily activated, and primary

pro-inflammatory cytokines such as TNF-aand IL-1 family mem-

bers are induced, and will in turn mediate the recruitment of dis-

tant subsets of the immune system to the skin which will induce

contact irritancy. During an allergic reaction, haptens and allergens

activate not only the resident structural cells but also resident anti-

gen-presenting cells which, in turn, migrate to local draining

lymph nodes and present the allergen to specific T-cells. These

cells differentiate into allergen-specific memory T-cells, re-circulateand on subsequent contact with the specific allergen, they extrava-

sate, get in contact with antigen-presenting cells, which present the

specific allergen to the effector memory T cells. These effector

memory T cells will then produce effector cytokines. In CHE we

find a predominance of the production of Type 1 effector cyto-

kines, which are represented by interferon-c. An excess of IL-4

production is also found in CHE lesions (Fig. 1).

There are bi-directional communication pathways between

structural cells of the skin and the immune system, and the traf-

ficking of leucocytes within the system is of major importance. A

family of small, cytokine-like proteins called chemokines play a

crucial role in directing the migration of leucocyte subsets to the

skin. Within the multistep process of leucocyte extravasation, the

chemokines which are expressed at the membrane of the endothe-

lial cells will mediate the adhesion of the leucocytes to the

endothelium, and are the stimulus for the leucocytes to perform

trans-endothelial migration from the blood vessel to perivascular

pockets. Subsequently, matrix-bound chemokine gradients will

further direct distinct leucocyte subsets from perivascular pockets

to sub-epidermal or intra-epidermal locations.

These situations can be reproduced in the laboratory in mice

models where distinct molecular signatures differentiating irritancy

and allergy can be elucidated.47 Independent of overall skin

inflammation, it has been found that a particular set of interferon-

cinducible chemokines, CXCL9 and CXCL10 are elevated only in

allergic contact eczema, but not in the irritant form. In contact irr-

itancy primary pro-inflammatory cytokines TNF-aand IL-1 fam-

ily members play a major role, and a non-allergy specific

chemokine CCL20 is elevated.

Alitretinoin may interfere at different steps in the inflammation

process seen in chronic contact eczema: (i) at the level of chemoki-

ne production, (ii) at the level of leucocyte activation and (iii) at

the level of antigenallergen presentation.Recent data have shown that within structural cells, alitretinoin

markedly suppresses the expression of chemokines thought to be

pathogenically relevant, suggesting that the drug may impair the

recruitment of the distinct leucocyte subsets to sites of skin inflam-

mation. Via this mechanism, alitretinoin may interfere with the

initiation as well as the maintenance of contact eczema lesions.

In contrast to isotretinoin, alitretinoin also markedly impairs

mixed leucocyte reactions. Detailed flow cytometric analyses

have shown significant dose-dependent suppression of activation-

Irritant

Hapten

Lymph Node

Figure 1 Skin immune system.




8/21

associated molecules on the surface of activated T cells by alitretin-

oin. Alitretinoin has also been shown to suppress leucocyte activa-tion in a dose-dependent manner.

The interaction of the antigen-presenting cell with the memory

T cell is crucial for the differentiation and activation of the latter,

and for the amplification of the immune response within the skin.

For the effective activation of the lymphocyte, the dendritic cell

has to provide co-stimulatory molecules. Without those the lym-

phocyte becomes tolerant and will not be activated. Alitretinoin

has been shown to significantly suppress the expression of these

co-stimulatory molecules on the surface of the antigen-presenting

cells.

In conclusion alitretinoin may interfere at different steps in the

inflammation process seen in chronic contact dermatitis (Fig. 2):

1 At early phases, alitretinoin may interfere with cytokine-

induced chemokine production in structural cells of the

skin and interfere with the recruitment of pathogenic leuco-

cyte subsets to the skin.

2 In leucocytes, alitretinoin may modulate activation pro-

cesses and interfere with the upregulation of the co-stimula-

tory molecules. In turn, effective antigen presentation might

be altered, leading towards impaired leucocyte activation,

proliferation and expansion.

These first insights into the mechanisms of action of alitretinoin

may help in the understanding of its clinical efficacy and provide

perspectives for future indications.

Toctino

(oral alitretinoin) a new

treatment for severe CHE: efficacy in

pivotal clinical trial

Dr C. Lynde

Alitretinoin is currently the only evidence-based therapy option

for patients with severe CHE unresponsive to potent topical corti-

costeroids.

Alitretinoin has been studied in a large randomized, multicen-

tre, placebo-controlled, double-blind study in 111 dermatology

clinics in Europe and Canada. The BACH study (Benefit of Alitre-

tinoin in Chronic Hand Eczema), is the largest controlled trial in

CHE to date.48 A total of 1032 patients with severe CHE unre-

sponsive to topical corticosteroids were randomized in a 2 : 2 : 1

ratio to alitretinoin 10 mg (n = 418), 30 mg (n= 409) or placebo

(n = 205). The drug was administered orally once daily for up to

24 weeks to determine whether alitretinoin was superior to pla-

cebo in reducing the signs and symptoms of CHE.48 Throughout

the study, patients were provided with a standardized emollient to

apply several times a day. No concomitant topical or systemic

medicated treatment for CHE was allowed during treatment or

during the relapse-observation period. The primary endpoint was

the percentage of patients with a physicians global assessment

(PGA) rating of clear or almost clear hands (defined as

response). Secondary endpoints included patients global assess-

ment (PaGA), Modified Total Lesion Symptom Score (mTLSS),extent of disease, time to response and time to relapse. Safety was

assessed for all patients during a follow-up period of 4 weeks, and

responders were observed for relapse for 24 weeks after the end of

therapy. Patients with psoriatic lesions were excluded from the

study as were patients with atopic eczema whose condition

required a medicated treatment.

The PGA attempts to offer an objective assessment of disease

severity. Using a pre-defined guide, physicians rate patients sever-

ity of CHE according to a 5-point scale from clear to severe

(Table 9). A validated photographic guide is used to support con-

sistent and reproducible grading of overall CHE severity for the

PGA (Fig. 12).The mTLSS is a composite measure of the intensity of seven

individual CHE signs and symptoms erythema, oedema, desqua-

mation, fissures, hyperkeratosislichenification, prurituspain and,

vesicles. Each sign or symptom is rated by the physician on a 4-

point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe), with

the mTLSS calculated as the sum of assigned individual scores

with a maximum value of 21 (most severe disease) and a mini-

mum of 0 (no disease) (Table 10).

Male patients or female patients (either post-menopausal or

prepared to enter a pregnancy prevention programme) aged 18

75 years were enrolled. Patients were eligible for inclusion provid-

ing their disease was persisting for at least 6 months since initial

diagnosis, was rated severe according to the PGA and was unre-sponsive to avoidance of irritants and allergens, non-medicated

treatments and standard therapy including potent topical corticos-

teroids. All types of CHE were eligible for inclusion including

hyperkeratotic, vesicular (e.g. pompholyx) and fingertip.

Results

The patient groups were well matched with regard to demograph-

ics and disease characteristics (Table 2). The majority of patients

had hyperkeratotic CHE, however, phenotypes were not mutually

Figure 2 Effects of alitretinoin.




9/21

exclusive and the majority of patients with hyperkeratosis also had

signs of inflammation such as erythema and vesicles. The average

age of patients enrolled in the trial was relatively high. A lower

proportion of younger women than would be expected in the gen-

eral patient population were enrolled, as alitretinoin, like other ret-

inoids, is highly teratogenic and therefore requires the

implementation of a strict pregnancy prevention programme

amongst women of child-bearing potential.

Response rates for achieving clear or almost clear hands were

markedly higher in the alitretinoin 30 mg (48%; 195 of 409patients) and 10 mg (28%; 115 of 418) groups compared with pla-

cebo (17%; 34 of 205) (Fig. 3). Complete clearance was achieved

in a higher proportion in the alitretinoin 30 mg (n = 90) and

10 mg (n = 39) groups compared with placebo (n = 6). Placebo

response rates were comparable with those seen in other dermatol-

ogy studies. Inclusion in the placebo group entailed intense overall

management including use of emollients and clinical consulta-

tions, which are both likely to have been more rigorous and fre-

quent than patients normal routine.

The study was not powered to detect differences in efficacy

between differing classifications of CHE, but it appears that the

activity of alitretinoin was not limited to patients with any distinct

combination of eczema signs and symptoms (Table 3). Response

rates were highest for the 85% of patients who were classified as

having hyperkeratotic CHE at baseline. However, CHE types werenot mutually exclusive, as nearly all (99%) of CHE patients classi-

fied as predominantly hyperkeratotic by the investigator had also

signs of inflammation, such as erythema and vesiculation.

The time to response was significantly shorter in the alitretinoin

30 mg group compared with alitretinoin 10 mg or placebo

(P< 0.001). Figure 4 depicts the cumulative response for the three

treatment arms over the study period. By week 12, there was a

clear separation in response between all the three groups (4% in

placebo vs.11% in 10 mg vs. 28% in 30 mg). The median time to

response (clear or almost clear hands) for patients responding

to treatment with alitretinoin 30 mg was 12.1 weeks, which is an

Figure 3 Patients with clear or almost clear hands at the end

of treatment.

Table 2 Patient demographics

Placebo

Alitretinoin

10 mg 30 mg

Patients in ITT population (n) 205 418 409

Mean age (years) 47.9 47.3 48.5

Sex (% male) 59 56.9 54.5

Females


10/21

encouraging result for patients whose condition could not be suffi-

ciently managed over many years.

There was a good correlation between the primary efficacy

parameter (PGA) and the PaGA (correlation coefficient 0.82; Ken-

dalls tau) (Fig. 5). This consistency may reflect the use of a cate-

gorical scale of severity instead of an estimated degree of

improvement, and lack of ambiguity in the definition of response,

corresponding to complete or nearly complete resolution of previ-

ously severe disease.

Alitretinoin 30 mg produced a median change from baseline in

mTLSS of 58% at week 12 and 75% by week 24 (Fig. 6).Improvements were seen in all seven of the individual signs and

symptoms that make up the mTLSS, and none showed plateaux at

the end of the study, suggesting extension treatment beyond

24 weeks may lead to further responses of clear or almost clear

hands (Fig. 7).

Extent of disease was evaluated and was defined as the per-

centage of hand area (with 100% defined as the palmar and dor-

sal aspects) affected by disease. The median reduction in extent

of disease was significantly reduced following treatment with ali-

tretinoin 30 mg compared with placebo (75% vs. 33%;

P< 0.001).

Conclusions

The results from the BACH study show that oral alitretinoin is

highly effective in treating severe CHE unresponsive to potent top-

ical corticosteroids. A 75% reduction in signs and symptoms of

CHE after 24 weeks was observed following alitretinoin treatment

with 48% of patients having clear or almost clear skin within

1224 weeks. All individual symptoms of CHE improved and ali-

tretinoin was efficacious in all forms of CHE, with highest

response in hyperkeratotic disease.

With alitretinoin, patients and physicians will have, for the first

time, a convenient, safe and effective oral treatment licensed forsevere cases of CHE, when topical corticosteroids have not led to

improvement, and patient quality of life is severely affected.

Toctino (oral alitretinoin) a new

treatment for severe CHE:

retreating patients with CHE

Professor P. Elsner

In the BACH study, alitretinoin demonstrated high efficacy in the

treatment of severe CHE in patients who were unresponsive to

treatment with potent topical corticosteroids.48

Patients who had responded by the end of the BACH trial werefollowed up for relapse during a 24-week observation period.

Relapse was defined as an mTLSS score 75% that of their baseline

score in the BACH trial. Only one-third of the BACH responders

relapsed within the 24-week follow-up period (116344 respond-

ers; 33.7%).

At the end of the follow-up 24-week observation period, two

categories of patients were eligible to take part in a retreatment

study, designed to evaluate the efficacy and safety of a second 12-

to 24-week course of oral alitretinoin:49 (i) patients who did ini-

Figure 4 Time to response [Intent-To-Treat (ITT) population].

Figure 5 Correlation between physicians global assessment

and patients global assessment scores.

Figure 6 Improvement in signs and symptoms over time: med-

ian % reduction in mTLSS (ITT population).




11/21

tially respond but relapsed within 24 weeks after completion oftreatment (cohort A); (ii) patients who did not respond and were

rated mild or moderate according to the PGA at end of the BACH

study (cohort B).

Results from cohort A

One hundred and seventeen patients were included in a double-

blind, randomized, placebo-controlled, multicentre study and were

randomized to receive their previous treatment (either alitretinoin

10 mg or 30 mg daily) or placebo, for up to 24 weeks.

Baseline patient characteristics are presented in Table 4. Subjectswere predominantly Caucasian with a mean age of between 49

and 52 years. The majority of patients had hyperkeratotic CHE,

but categories were not mutually exclusive.

The primary efficacy parameter was the PGA and response was

defined as clear or almost clear hands at the end of treatment.

Response rates were 79.6% (n = 39) in patients retreated with ali-

tretinoin 30 mg compared with 8.3% (n = 2) for placebo

(P< 0.001) (Fig. 8). In patients retreated with alitretinoin 10 mg

response rates were 47.6% (n = 10) compared with 10.0% (n= 1)

Figure 7 Individual components of the mTLSS in patients responding with clear or almost clear hands in the alitretinoin 30 mg

group.




12/21

in the placebo group. Of the responders in the alitretinoin 30 mg

arm, 42.9% (n= 21) had a PGA rating of clear and 21 patients

responded by week 12. Of the responders in the alitretinoin 10 mg

arm, 20% (n= 2) had a PGA rating of clear and three patients

responded by week 12. Amongst the 13 patients in this trial whohad responded to placebo in the initial BACH study, nine patients

(69.2%) responded to placebo again.

Secondary endpoints were consistent with PGA results. The

median percentage reduction in mTLSS scores was 92.3% for

patients receiving alitretinoin 30 mg and 70.8% for patients receiv-

ing 10 mg. PaGA results were consistent with those observed for

the PGA with 75.5% of patients treated with alitretinoin 30 mg

and 38.1% in the 10 mg group reporting clear or almost clear

hands. Median percentage reduction in the extent of disease was

90.0% for patients in the 30 mg group and 46.7% for patients

who received alitretinoin 10 mg.

Results from cohort B

Patients who did not respond with clearalmost clear hands in the

BACH study, and who were presenting with mild or moderate

CHE at the end of the study were eligible to receive a second

course of alitretinoin treatment (cohort B). These patients were

included in an open-label, multicentre study design and received

30 mg of alitretinoin independent of their previous treatment inthe BACH trial for up to 24 weeks. Patient demographics for

cohort B are presented in Table 5.

Overall, approximately half of the patients, who did not

respond to an initial course of treatment, responded toFigure 8 Response rate at end of treatment in patients whorelapsed after initial treatment of severe chronic hand eczema

(physicians global assessment) (cohort A).

Table 4 Baseline patient characteristics (cohort A)

Placebo

Alitretinoin

10 mg

Alitretinoin

30 mg

Patients in ITT population (n) 47 21 49

Mean age (years) 50.4 49 52

Sex (% male) 51.1 71.4 51

Females


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retreatment with alitretinoin 30 mg. The response rates in cohort

B by previous treatment in the BACH trial were 50.4% for alitre-

tinoin 10 mg, 39.1% for 30 mg and 50.9% for placebo (Fig. 9).

Results for cohort B suggest that either a higher dose or a longer

treatment period may benefit patients who have initially failed to

respond to alitretinoin treatment.

Conclusion

The majority of patients with CHE who had previously responded

to alitretinoin treatment, i.e. who had achieved clear or almost

clear hands and had relapsed within 6 months, responded to a

second course of treatment.

Patients who had not responded to an initial course of alitretin-

oin treatment, be it 10 mg or 30 mg, in the 24 week study period,

did achieve clear or almost clear hands in half of the cases fol-

lowing an additional treatment course of alitretinoin 30 mg for up

to 24 weeks.

Toctino (oral alitretinoin) a new

treatment for severe CHE: safety in

clinical trials

Dr R. Bissonnette

The efficacy of alitretinoin in the treatment of severe CHE has

been studied via safety and tolerability assessments performed

throughout the clinical development programme. This section will

review only the large phase III clinical trial data, however, safety

results from earlier phase II trials are consistent with the data pre-sented here.

Three trials are discussed in this section:

Patients in all three studies had severe CHE unresponsive to

potent topical corticosteroids.

[Study A] The BACH study conducted in 111 centres in Europe

and Canada a double-blind, randomized, placebo-controlled,

parallel-group trial in 1032 patients who received alitretinoin

10 mg (n = 418) or 30 mg (n= 409), or placebo (n = 205) once-

daily for 12 or 24 weeks depending on response to treatment.

Patients were provided with a standardized emollient to apply sev-

eral times a day. No concomitant topical or systemic medication

for CHE was allowed during treatment or during the relapse-

observation period. Alitretinoin intake could be interrupted fortolerability reasons, but dose reductions were not allowed.48

[Study B] An open-label, non-comparative, single fixed-dose

study in 249 patients from 37 centres in Europe and Canada.

Patients received oral, once-daily treatment with alitretinoin

30 mg for up to 24 weeks. As in the previous BACH study, dose

interruptions were allowed if necessary to manage AEs. Unlike the

previous study, dose reductions were allowed to emulate the dose

adjustments for the management of tolerability that are likely to

occur in clinical practice with oral retinoids.50

[Study C] A double-blind, placebo-controlled, randomized

study that included patients who responded to initial treatment in

the BACH study and relapsed within 24 weeks. One hundred and

seventeen patients were re-randomized to a second course of the

same dose of alitretinoin or placebo for up to 24 weeks.

Alitretinoin was well tolerated in the treatment of patients with

severe CHE unresponsive to treatment with topical corticosteroids.

Special safety assessments were performed in the BACH study

(study A) and in the re-treatment study (study C). No differences

in psychiatric questionnaires (Centre for Epidemiological Studies

Depression Scale, General Health Questionnaire) or in the inci-

dence or severity of psychiatric AEs were observed between the

treatment groups. Similarly, bone density assessments or skeletal

radiographs did not reveal any effect of dosing on bone minerali-

zation or extraosseous calcifications. Beside dry eyes no other

treatment related effects were observed in ophthalmological assess-

ments. In addition, electroretinograms were performed in a phar-

macology study involving 32 patients exposed for 24 weeks. Noeffect on retinal function was observed. In the clinical programme,

two fatalities occurred in patients receiving the 10 mg dose. Both

events (myocardial infarction and acute cardiac failure) were

assessed as unrelated to the treatment.

Adverse events

Adverse events (AEs) were generally dose-dependent, manageable

and consistent with other compounds in the retinoid class. Head-

ache was the most commonly occurring AE in patients treated

with alitretinoin 30 mg, and the most common reason for study

withdrawal (Table 6).

[Study A] Headache was reported as an AE in 6.4%, 10.8% and19.8% of patients taking placebo, alitretinoin 10 mg or alitretinoin

30 mg respectively. Headache led to 17 (4.1%) patient withdrawals

in the 30 mg group, six (1.4%) in the 10 mg group, and one

(0.5%) in the placebo group. No other AE caused more than two

withdrawals in any group. There were seven cases (1.7%) of head-

ache rated as severe with alitretinoin 10 mg, compared with 19

(4.6%) with 30 mg, and none with placebo.

[Study B] A total of 18.5% of patients reported headache as an

AE. Out of 21 (8.5%) of patients who withdrew because of AEs,

nine (3.6%) were because of headache. Severe headache was

reported in 6% of alitretinoin 30 mg patients. In 29 cases, head-

ache was managed using analgesics alone (paracetamol or ibupro-

fen). Headache led to dose reduction to 10 mg in 15 patients (sixwere subsequently increased to 20 mg or 30 mg); two patients

interrupted treatment because of headache. Time of onset of

headache showed no specific pattern; two cases occurred prior to

first exposure to drug, 34 cases within 10 days of treatment initia-

tion and 28 cases within 3 days of treatment initiation. Of the

three serious AEs occurring in the open-label study, only one was

considered to be remotely treatment related a case of angioneu-

rotic oedema that resolved following discontinuation of treat-

ment. The pathophysiology of these headaches (as with other




14/21

retinoids) is unknown. The headaches were described predomi-

nantly as tension-type headaches and tended to occur early in

treatment.

[Study C] Headache was the most frequently occurring AE and

all reports of headache occurred in the 30 mg group (14.0%). A

single patient (2.0%) from the 30 mg group withdrew because of

headache. There were two (4.0%) cases of headache rated as severe

by the investigator in the alitretinoin 30 mg group. No severe

headaches were reported in either the placebo or alitretinoin

10 mg groups.

Overall, in the three studies, mucocutaneous effects (any of the

following: dry lips, cheilitis, dry skin, dry mouth, dry eyes)

occurred in approximately 10% of patients. This is a lower inci-

dence than that reported for other retinoids.

Marked laboratory abnormalities

[Study A] Observed laboratory abnormalities were typical effects

of retinoids. Increases in serum cholesterol and triglyceride levels

were the most commonly reported marked abnormalities

(Table 7). These changes either resolved or improved markedly

within 4 weeks after the end of therapy. Three cases of hypercho-

lesterolemia were either present at baseline or were non-fastingvalues. About half of the patients with marked abnormal increases

in serum cholesterol or triglyceride levels in this retreatment study

had similar abnormalities during the initial BACH trial. Reduced

thyroid-stimulating hormone (TSH) levels were reported in the

alitretinoin 30 mg group (Table 7). Reductions in TSH levels were

not always accompanied by corresponding reductions in T4. No

clinical hypothyroidism was observed and no patient required any

clinical intervention during the study (such as dose interruption,

supplementation with thyroid hormones, etc.). Unlike other reti-

noids, there was little or no apparent effect on hepatic enzyme or

bilirubin levels.

[Study B] The profile of laboratory abnormalities in Study B

was similar to that of the alitretinoin 30 mg group in study A.

[Study C] In the retreatment study, where patients who initially

responded to alitretinoin but later relapsed were exposed to a sec-

ond 1224 week course of drug, alitretinoin remained well toler-

ated. No significant late-arising toxicities were observed (255

patients received alitretinoin treatment for a maximum period of

48 weeks).

Table 6 Common adverse events reported in at least 3% of patients in any treatment group

Treatment emergent AEs

3%

in any group

Study A Study B Study C

Placebo

(n= 203)

Alitretinoin

10 mg

(n= 418)

Alitretinoin

30 mg

(n= 410)

Alitretinoin

30 mg

(n= 248)

Placebo

(n= 46)

Alitretinoin

10 mg

(n= 21)

Alitretinoin

30 mg

(n= 50)Patients with any AEs 49.8 51.7 59.5 54.4 26.1 42.9 44

Nasopharyngitis 6.9 5.3 5.9 9.3 4.3 4.8 4

Upper RTI 2 1.2 2.2 1.2 0 0 2

Erythema 1.5 1.7 7.3 2 0 4.8 12

Eczema 4.9 3.8 3.2 1.2 2.2 0 2

Dermatitis 2.5 1.7 1.7 0.8 2.2 4.8 0

Pruritus 2 0.7 0.7 3.2 0 0 0

Headache 6.4 10.8 19.8 18.5 0 0 14

Dry lips 2 2.2 3.7 1.2 2.2 0 2

Nausea 1.5 2.4 3.4 2.4 0 0 2

Dry mouth 1 2.4 2.4 1.6 2.2 4.8 4

Flushing 1 1.2 4.4 6.9 0 0 0

Blood CPK elevated 2 1.9 3.2 2.4 0 0 2Blood triglyceride elevated 0 0.7 2.9 0.8 0 4.8 0

AE, adverse event; CPK, creatinine phosphokinase.

Table 7 Marked laboratory abnormalities in study A

Laboratory parameter Placebo

Alitretinoin

10 mg

Alitretinoin

30 mg

TSH high

>7.4 mUL (age 20 years) 0 0 150 (2.0)

>6.3 mUL (age >20 years)

TSH low

5.66 mmolL)

133 (3.0) 117 (5.9) 538 (13.2)

AST high

>90 UL (Male) 0 0 250 (4.0)

>72 UL (Female)

Bilirubin high (>37lmolL) 0 0 150 (2.0)

Values in parentheses are in percentages.




15/21

Conclusions

Throughout the clinical development programme, alitretinoin has

been subjected to rigorous safety assessments. Alitretinoin is well

tolerated in the treatment of patients with severe CHE unrespon-

sive to topical corticosteroids at doses up to 30 mg. AEs are

dose-dependent, manageable and consistent with retinoid class

effects headache being the most commonly occurring AE. As

expected, the incidence of mucocutaneous effects seen in these

trials is lower than that reported for other retinoids including iso-

tretinoin, occurring in less than 10% of patients receiving the

30 mg dose. No relationship between alitretinoin treatment and

any psychiatric disorders were seen and there were no reports of

sticky skin, desquamation, hair loss or photosensitivity. No signifi-

cant late-arising toxicities were observed in patients receiving a

second treatment cycle or whose treatment was continued for a

further 1224 weeks. These findings suggest that a second course

of alitretinoin is well tolerated.

Advancing CHE management inclinical practice

CHE treatment guidelines and their

role in good clinical practice

Professor T. L. Diepgen

Given the lack of an accepted classification for HE, the use of

EBM can provide a more comprehensive method of classifica-

tion that allows the different mechanisms, morphological forms

and manifestations of HE to be systematically catalogued and

evaluated within the framework of the currently available treat-

ment options.

Evidence-based medicine

Often clinical experience does not give sufficient evidence to

guide clinical practice it is a very valid source of information but

it is not systematic and is often not supported by rigorous clinical

trial data. Expert opinions can dominate in the absence of evi-

dence, and non-systematic reviews can be biased. The abundance

of medical literature can make it difficult for any individual physi-cian to be fully up-to-date with all of the current work within a

field and this is where EBM can provide valuable support.

The conscientious, explicit, and judicious use of current best

evidence in making clinical decisions about the care of individual

patients was how Dr David Sackett, the father of EBM, described

this area of medicine. EBM is not cookbook medicine, it is a pro-

cess by which evidence is integrated with patient preferences and

provider expertise (including knowledge of what makes a patient

unique). Systematic reviews play a crucial part in this evidence-

based system. The Cochrane Collaboration is an international

organization formed in 1993 that aims to help people make well

informed decisions about healthcare by preparing, maintaining

and promoting the accessibility of systematic reviews of the effects

of healthcare interventions. The Cochrane Skin Group (formed in

1996) is part of this collaboration. Systematic reviews are charac-

terized by, clear and focused study questions, explicit definition of

study criteria anda prioriprotocol for collating evidence. They are

an exhaustive search of the available literature (including hand-

searching and unpublished studies) provide explicit or implicit

factoring of study quality and are the most comprehensive

resource for therapy questions.

Guidelines

The interplay of factors involved in clinical decision-making are

summarized below (Fig. 10). Guidelines are helpful in aiding the

physician in the evaluation of all of these factors and in allowing

them to make more informed clinical decisions. They also giveweight to physicians recommendations and can help to influence

policy makers and reimbursement agencies whilst diffusing poten-

tial litigations. Guidelines are also useful in delivering novel treat-

ments to patients far faster than a system of filtration from

opinion leaders, through the medical hierarchy.

German guidelines

Guidelines for the management of HE have recently been devel-

oped in Germany in association with the German Dermatology

Association (DDG).51 These guidelines recommend the use of ali-

tretinoin for persistent or chronic relapsing HE when class 24

topical glucocorticoids and

or UV therapy have failed.

Classification

There is no simple definition of HE. A comprehensive classifica-

tion should take into account the different causative mechanisms

Figure 10 Factors that enter into clinical decisions.




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(exogenous vs. endogenous), various morphological forms (such

as vesicular [dyshidrotic], hyperkeratoticrhagadiform and num-

mular), and different sites of HE manifestation (such as dorsal,

palmar and interdigital HE). These are summarized below

(Table 8).

Recommendations

The recommendations from the German guidelines are summa-

rized below.

1. History taking

Occupational

Exposure profile

Known allergies

2. Diagnostic procedures

Allergen tests (patch testing, skin prick testing)

Histological examination where appropriate

Rule out possible fungal infections

Table 8 Classification of hand eczema: overlapping disease

entities, multifactorial aetiologies and mixed forms are common

Aetiology (types of HE)

Irritant (subtoxic cumulative HE)

Allergic HE

Atopic HE

Protein contact dermatitis

Other (genuine pompholyx type, tylotic HE, etc.)

Site

Dorsum

Palm

Sides of the fingers

Fingertips

Finger webs

Wrists

Morphology

Dyshidrotic (vesicular)

Erythema, desquamation

Hyperkeratoticrhagadiform (=tylotic)

Nummular

HE, hand eczema.

Step 4: Persistent or chronicrelapsing HE

Step 3: Moderate HE

Step 2: Mild HE

Step 1: Dry skinTopical background therapy: skin hydration,

emollients,

avoidance or reduction of triggers

+ antipruritic and antiseptic

drugs, Class 2 topical

glucocorticoids and/or topicalcalcineurin inhibitors

+ Class 24

topical

glucocorticoids

+ systemic

immunomodulatorytherapy (eg alitretinoin

or ciclosporin A)

Figure 11 Therapeutic options.




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3. Preventative measures

Primary prevention education regarding behavioural pre-

vention strategies, control of individual risk factors, and

environmental prevention strategies

Secondary prevention dermatologist procedures to spot

skin changes early on, to enable early institution of pre-

ventative measures

Tertiary prevention concerted (inoutpatient) and inter-

disciplinary (occupational dermatology, industrial health,

health educational, occupational therapeutic, psychologi-cal, and trade association-administrative) interventions

4. Therapy (see Fig. 11)

Using Toctino (oral alitretinoin) in

day-to-day clinical practice answers

to some commonly asked questions Oral treatment with alitretinoin treatment is started at a

dose of 30 mg. The dose can be reduced for the

management of adverse reactions. Up-titration is an

option for patients whose dose was reduced or who were

started on a lower dose, e.g. for pre-existing cardiovascu-

lar conditions.

The absorption of alitretinoin is greatly affected by food.

Alitretinoin therefore should always be taken with a meal.

There is no need for dose adjustment according to body

weight as there is no correlation between body weight and

drug exposure or clinical response.

Clinical studies did not indicate a relationship betweenpsychiatric disorders and alitretinoin medication.

No photosensitivity has been observed following alitretin-

oin treatment.

As in the case of other retinoids, serum cholesterol and triglyce-

rides should be monitored. The laboratory test interval may be

adapted to the response of the patients laboratory values to the

medication. Patients with cardiovascular risk factors require closer

monitoring, and if the risk pre-dates treatment initiation, an initial

dose of 10 mg is recommended.

Table 9 Physicians global assessment (PGA)43

PGA severity Features Intensity Area involved

Severe Erythema, scaling, hyperkeratosislichenification At least one moderate or severe >30% of affected hand surface

Vesiculation, oedema, fissures, prurituspain At least one severe

Moderate Erythema, scaling, hyperkeratosis

lichenification At least one mild or moderate 1030% of affected hand surfaceVesiculation, oedema, fissures, prurituspain At l east one moderate

Mil d Erythema, scali ng, hyperkeratosi slichenification At least one mild Less than 10% of affectedhand surfaceVesiculation, oedema, fissures, prurituspain At least one mil d

Almost clear Erythema, scaling, hyperkeratosislichenification At least one mild Less than 10% of affected

hand surfaceVesiculation, oedema, fissures, prurituspain Absent

Clear Erythema, scali ng, hyperkeratosi slichenification Absent Not detectable

Vesiculation, oedema, fissures, prurituspain Absent

Figure 12 Photographic severity guide used in physicians global assessment scoring.10




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Conclusions

Severe CHE is a distressing illness that often runs a long-lasting,

relapsing course that causes significant burdens for both patients

and society. Current treatment strategies are extremely limited and

there is a clear and unmet medical need for an effective intermit-

tent therapy to treat this chronic condition.

Alitretinoin is an endogenously occurring physiological vitamin

A derivative, and is at present the only product licensed for severe

CHE unresponsive to potent topical corticosteroids. The largest

study in CHE to date (BACH) showed that alitretinoin is highly

effective in clearing severe CHE. Alitretinoin has been shown to be

notably effective in the long-term management of CHE and is well

tolerated with a good safety profile. Given the chronic nature of

the disease, management of long-term effects is paramount, and

alitretinoin provides a breakthrough in this area because of its evi-

dence-based long-term efficacy combined with good tolerability.

Like other retinoids, alitretinoin is a strong teratogen. Strict adher-

ence to pregnancy prevention measures including pregnancy test-ing, contraceptive counselling and effective contraception are

required before, during and 1 month after cessation of treatment

for women of childbearing potential.

Alitretinoin offers patients with CHE unresponsive to potent

topical corticosteroids an effective, systemic, intermittent treat-

ment for the long-term management of their chronic relapsing

disease.

Appendix

Severity assessment tools

Details of the assessment tools for measuring CHE severity in thealitretinoin clinical trials are included below.

Physicians global assessment

The PGA provides an objective assessment of disease severity.

Using a pre-defined guide, physicians rate patients severity of

CHE according to a 5-point scale from clear to severe (Table 9).

Photographic severity guide

A recent investigation asked five experts to grade 50 photographs

of CHE, first individually, then as a consensus-building group, to

select the photographs included in the guide. Following this, a val-

idation session with 11 different dermatologists evaluating 28

patients showed a high level of inter-rater reliability and testretest

reproducibility (Fig. 12).

Modified total lesion symptom score

The mTLSS is a composite measure of the intensity of seven

individual CHE symptoms. Scores are summed, with a maxi-

mum value of 21 (most severe disease) and a minimum of 0

(no disease). Individual symptom rating scores are provided in

Table 10.

Conflicts of interest

TL has been working as a consultant for Basilea Pharmaceutica

International Ltd. TLD has received lecture and consultancy

fees from Basilea Pharmaceutica International Ltd. HM has

worked as a consultant for Basilea Pharmaceutica International

Ltd. JE has received lecture and consultancy fees from Basilea

Pharmaceutica International Ltd. RG-B has been reimbursed

by Basilea Pharmaceutica International Ltd. for attendance at

advisory boards; JM is an employee of Basilea Pharmaceutica

Table 10 Modified total lesion symptom score

Erythema

0 = Absent

1 = Faint erythema

2 = Prominent redness3 = Deep intense red colour

Scaling

0 = Absent

1 = Slight flaking over limited areas, mostly fine scales

2 = Flaking over widespread area(s), coarser scales

3 = Desquamation covering over 30% of the hand,

with coarse thick scales

Lichenificationhyperkeratosis

0 = Absent

1 = Mild thickening with exaggerated skin lines over limited areas

2 = Palpable thickening over widespread area(s)

3 = Prominent thickening over widespread area(s) with

exaggeration of normal skin markings

Vesiculation

0 = Absent

1 = Scattered vesicles affecting up to 10% of hand, without

erosion

2 = Scattered or clustered vesicles affecting up to 30% of hand,

without visible erosion or excoriation

3 = High density of vesicles extending over large area(s), or with

erosion or excoriation

Oedema

0 = Absent

1 = Dermal swelling over less than 10% of hands

2 = Definite dermal swelling over more than 10% of hand

3 = Dermal swelling with skin induration over widespread area(s)

Fissures

0 = Absent

1 = Cracked skin affecting a small area of the hand

2 = Cracked skin affecting multiple areas of the hand and causing

pain

3 = One or more deep fissures and causing bleeding or severe

pain

Prurituspain

0 = Absent

1 = Occasional, slight discomfort a few times per day

2 = Intermittent, causing discomfort frequently during the day

3 = Persistent or interfering with sleep




19/21

International Ltd. BH has worked as a consultant for Basilea

Pharmaceutica International Ltd. CL has been reimbursed by

Basilea Pharmaceutica International Ltd. for consultant work

as a principle investigator; PE has been reimbursed by Basilea

Pharmaceutica International Ltd. for consultant work; RB has

been a consultant and an investigator for Basilea Pharma-

ceutica International Ltd. The presented work has been sup-

ported by a research grant from Basilea Pharmaceutica

International Ltd.

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