M Farizon

S Farizon

T D Ouaskit

Märk

Absolute total and partial cross sections for ionization of nucleobases by proton impact in the Bragg peak velocity range

1 Absolute total and partial cross sections for ionization of nucleobases by proton impact in the Bragg peak velocity range J. Tabet, S. Eden1 , S. Feil, H. Abdoul-Carime, B. Farizon, M. Farizon, S. Ouaskit2 , T.D. Märk 3Université de Lyon, F-69003, Lyon, France; Université Lyon 1, Villeurbanne; CNRS/IN2P3, UMR5822, Institut de Physique Nucléaire de Lyon; F-69622, Villeurbanne.

Abstract: We present experimental results for 80 keV proton impact ionization of nucleobases (adenine, cytosine, thymine and uracil) based on an event by event analysis of the different ions produced combined with an absolute target density determination. We are able to disentangle in detail the various proton ionization channels from mass analyzed product ion signals in coincidence with the charge-analyzed projectile. Thus, for the first time, cross sections and fragmentation patterns are compared for direct ionization (with no charge transfer between the target molecule and the projectile) and for single electron capture (with projectile neutralization) in proton-nucleobase collisions. In addition we are able to determine a complete set of cross sections for the ionization of uracil by 20-150 keV protons Further to their fundamental importance in collision physics [START_REF] Mcdaniel | Atomic Collisions[END_REF], molecular ionization and dissociation processes are of great interest in diverse areas of science ranging from plasma physics to radiation damage in biological tissues [START_REF]Molecules of Biological Interest in the Gas Phase, Experimental Tools and Quantum Chemistry[END_REF]. Today it is recognized that radiation damage in biomolecules, notably the formation of DNA strand breaks, is not only the result of a single interaction of the primary ionization projectile with the molecules involved, but also due to the simultaneous and consecutive action of the primary and the secondary species [START_REF] Sanche | [END_REF]. A detailed knowledge of ionization and dissociation processes involved including the various cross sections is a must for a full understanding of radiation damage on a microscopic level (see e.g. [4,5]). This has led recently to an increased number of investigations on the interactions of the various primary and secondary species with DNA and its constituents. Gas and solid phase experiments have been carried out with isolated basic constituents of DNA (i.e., the nucleobases, phosphate, sugar, water subunits) involving target molecules and molecular compounds of increasing complexity. Many of these seminal studies have been devoted to the interaction of low energy electrons (e.g. see [6][7][8][9][10][11][12][13]). This work has led to major advances in understanding the role of the secondary low energy electrons in radiobiology with potential applications in radiotherapy [14].

In contrast with electron-induced processes, investigations concerning proton (or heavier ions, for example see [15,16]) interactions with DNA and its constituents are rather scarce and a number of important details have not yet been investigated. This is particularly intriguing as the interaction of protons in the keV energy range with building blocks of DNA is of great biological relevance in view of the ever increasing number of proton therapy facilities using MeV proton irradiation [17]. When these protons enter the tissue they are decelerated reaching Bragg peak energies. These tumor treatments exploit the Bragg peak maximum and its volume selectivity based on the intricate interplay of the various primary and secondary interaction processes. Despite being such a promising tool for cancer treatment, most proton interaction studies reported so far have been restricted either to a specific type of cross section or have involved targets consisting of atoms or small (atmospheric) molecules. Although numerous total electron capture cross sections are available for proton interactions with gases [18][19][20], only recently have complete sets of ionization cross sections (including the total and the partial cross sections for direct ionization and electron capture) been reported for protons (or hydrogen) collisions with condensable molecular targets such as H 2 O [21][22][23]. In 2003 Coupier et al. [24] reported the first mass spectrum for the direct ionization of uracil with 20 to 150 keV protons in comparison with electron impact ionization. Moretto-Capelle et al. [25] followed this up with an electron spectroscopy study obtaining double differential cross sections showing preferential emission of low energy electrons for 25-100 keV proton impact on gas phase uracil. Alvarado et al. [26] recently used a new experimental approach to directly measure the amount of internal energy present in deoxyribose dications after keV proton collisions with gas phase molecules. Finally, Le Padellec et al. [27] reported mass spectra for 100 keV proton impact ionization of gas phase cytosine, thymine and uracil.

In this letter we report on the application of a novel experimental set-up which allows us, on an event by event basis, to analyze in great detail proton impact ionization of nucleobases (adenine, cytosine, thymine and uracil) and to measure absolute partial and total single ionization cross sections as a function of the charge state of the projectile after the ionization event. Mass analyzed product ions were detected (providing fragmentation pattern data) in coincidence with the charge-analyzed projectile after the ionizing collision, i.e., H + detection after direct ionization (DI), neutral H 0 detection after single electron capture (EC), or H -detection after double electron capture [28,29]. The present study have become possible by the development of a temperature controlled Knudsen type molecular beam source with absolutely characterized target thickness. We are thus able to disentangle the various reaction channels in proton ionization of nucleobases and provide in addition absolute ionization and dissociation cross sections that are 'differential' in terms of the projectile state. This is the first time that absolute cross sections for proton ionization become available for targets which exist in the solid state (powder) under normal atmospheric conditions. In this letter we report on results involving positive product ion formation: direct ionization and single electron capture events.

The experimental apparatus is shown in Fig. 1. It consists essentially of five parts (partially shown in Fig. 1): Firstly, pure molecular hydrogen is ionized in a standard RFdischarge source [30]. Secondly, ions from the source are accelerated to 20-150 keV with an energy resolution ∆E/E of 0.01 [30]. Thirdly, the primary magnetic sector field shown in Fig. 1 is used as a mass-selector to produce a pure beam of protons which is followed by a parallel plate deflector allowing to detect the primary ion beam. Fourthly, the proton beam intersects a perpendicular effusive jet of sublimated nucleobase molecules and the cross-beam interaction region is coupled to a time of flight mass spectrometer. The effusive neutral target beam jet is produced by sublimating nucleobase powder samples (purchased from Sigma-Aldrich, minimum purity 99%) in a temperature controlled Knudsen type oven with a capillary exit of 1 mm diameter. The target thickness and distribution has been determined by combining mass measurements of the condensed nucleobases on a liquid nitrogen cooled aluminum plate mounted above the capillary exit with deposition patterns measured by optical interference analysis and calculated angular distribution profiles using Troitskii's vapor flow model [31]., the projectiles pass through a second (sector field type magnetic) mass selector combined with a multi-detector device using channeltrons that are located at different positions at the exit of the magnetic analyzer thus giving us information about the final charge state of the projectile (i.e., protons will be deflected and neutralized protons will be un-deflected by the magnet). We have checked single collision conditions by changing the densities of both beams. Finally, the nucleobase parent and fragment ions produced are extracted perpendicular to the direction of both, the projectile and the target beam, and then mass-to-charge analyzed in a time of flight analyzer in coincidence with the projectile signal at the multi-detector device. This allows us to record simultaneously the charged product ions produced in the target region and in coincidence for each single collision event the nature of the projectile (either H + or after electron capture neutral H) after the ionizing collision.

As examples, Fig. 2 shows mass spectra for single ion production events in 80 keV and 42 keV protons collisions with gas-phase uracil. Each mass spectrum was constructed after the interaction of about 10 7 -10 8 protons with the target beam producing about 10 4 product ions. Having applied our coincidence technique we can (in contrast to earlier studies with protons [24,27] and multiply charged ions [32]) distinguish between ions produced by direct ionization (DI) of uracil via U+H + → ions + H + and ions produced via electron capture (EC) via U+H + → ions + H. Besides parent ion production strong fragmentation is observed for both EC and DI leading to the appearance of five groups of fragment ions with neighboring mass numbers. In both ionization processes, the total fragment ion abundance is clearly much larger than the respective parent ion abundance. Table 1 includes uracil fragmentation branching ratios (fragment ion production / total ion production) for EC and DI at selected energies in the range 27-150 keV. In general, this branching ratio is larger for EC than for DI. This can be rationalized by arguing that in case of the direct ionization mechanism less energy is transferred to the molecular system than for electron capture. Moreover, this fragmentation branching ratio is for both cases rather independent of the kinetic energy (Table1); only at energies below about 40 keV does the fragmentation branching ratio increase strongly in the case of direct ionization (due to a strong decrease of the parent ion abundance), surpassing even that of the electron capture case. Finally, it should be mentioned that fragmentation patterns in case of direct ionization are rather similar to recent electron impact ionization mass spectra obtained in [33,34].

Extension to other nucleobases (first line in Table1) shows that the branching ratio between the two ionization modes, EC and DI, as expressed for instance by the branching ratio EC/EC+DI, is rather similar for these nucleobases, i.e. having values at 80 keV proton energy of 27.1 %, 27.6%, 26.6% and 25.4 % for adenine, cytosine, thymine and uracil, respectively. These values are also close to the corresponding branching ratio measurements for gas-phase water yielding 27.8% and 25.7% in two different studies [22,35]. The rather similar ratios for the nucleobases and water suggest that molecular details (for instance the rather differing ionization energies which are important input parameters for the absolute cross sections) are not decisive for the relative probability of these two reactions.

Besides these details on fragmentation and differences concerning the ionization mechanisms we are here also able to quantify the various reaction probabilities on an absolute scale for the first time. Figure 3 shows absolute cross sections in the energy range from 20 to 150 keV for proton ionization of uracil giving values for the total ionization cross sections and cross sections for those reactions proceeding via electron capture and those via direct ionization. Whereas the total cross section decreases in line with the Born Bethe high energy limit, the individual EC and DI contributions show different behavior, i.e., the EC cross section is decreasing strongly with increasing proton energy, whereas the DI cross section only decreases at higher energy approaching the Born Bethe cross section. This leads to a situation that around the Bragg peak at 20 keV the branching ratios are about 60% and 40% for EC and DI respectively, at around 35 keV the two cross sections are equal and at the highest energy studied here, at 150 keV, the branching ratios approach 10% for EC and 90% for DI. This behavior appears to be universal as can be seen from Fig. 4 where the uracil branching ratio for EC as a function of energy is compared to a number of other targets, including He [36] and some small molecules [22,35,36].

Finally, we are able here to compare experimental absolute cross section values for a series of nucleobases for the first time. Table 2 gives cross section values for 80 keV protons collisions with adenine, cytosine, thymine and uracil. Surprisingly, while three of these nucleobases show rather similar values for the total, the EC and the DI cross sections, respectively, in contrast cytosine has in all three cases a cross section which is smaller by a factor of about 3. A deeper insight into the details of this may be obtained by comparing these results with absolute electron impact ionization cross sections calculated recently [37,38] using the Deutsch-Märk (DM) and the Born and Bethe (BEB) methods, respectively. These semi-classical calculations take into account details of the electronic structure of the molecules under consideration and results obtained with DM and BEB agree in shape and magnitude. It is rather interesting to note that the maximum cross sections obtained in these calculations lie between 1.45 (uracil), 1.65 (cytosine) and 2.05 (adenine) x10 -15 cm 2 . This is quite different in the ordering and different in magnitude from the present proton results, i.e. the direct ionization cross sections for proton impact are about a factor of 4 (cytosine) to about 12 (uracil) larger than the electron ionization cross sections. This tendency is in accordance with our earlier observations in water when comparing electron cross sections with direct ionization cross sections taking into account the different projectile masses and comparing cross sections at the same velocities (see [22] and references therein) and has been attributed to target polarization effects. It was also argued that, at a fixed velocity, the lower kinetic energy of lighter projectiles reduces their cross sections relative to more massive counterparts as incident energy approaches the ionization potential of the target.

In conclusion, we have presented here the first results based on an event by event analysis for the proton impact ionization of gas phase nucleobases. This allows us to obtain a complete analysis in terms of the positive ions which are produced (and lost as in the case of reactions proceeding via electron capture by the proton). This experiment was possible after combining our high energy ion beam / multi-coincidence apparatus with a time of flight mass spectrometer operated in coincidence with the final projectile detection. This is the first time that a complete set of cross sections for the ionization of a target consisting of biologically relevant molecules (nucleobases) by proton impact has been obtained including the total and all partial cross sections, and, in addition, differentiating between the direct ionization and the electron capture mechanism. As this investigation yields a new wealth of information on proton impact ionization, we are confident that such measurements will provide an important impact and basis for future refinement of the theoretical treatment of these reactions and their influence in radiation biology.

Fig. 1 :

 1 Fig. 1: Schematic diagram of the experimental system

8 *

 8 Fragment ion production by EC Total EC (fragment + parent ions) The errors are generally greater for the branching ratios involving DI detection at 42 keV because the channeltron signal threshold had to be set quite close to the noise level.

Table 1 :

 1 Fig 3 : Absolute cross sections in the energy range from 20 to 150 keV for proton impact induced ionization of uracil including values for the total ionization cross sections and cross sections for those reactions proceeding via electron capture (EC) and those via direct ionization (DI). Open symbols designate measured absolute cross sections at 80 keV, filled triangles designate relative cross sections normalized to the absolute value at 80keV, lines designate fits to the corresponding data points after normalization. Electron capture ionization of uracil as a percentage of total ionization (electron capture + direct ionization) following proton impact in the energy range 27-150 keV. The data are compared to previous results for H 2 O[22,35], and for He, CH 4 , CO 2 , and O 2[36]. Branching ratio between the two ionization modes, EC and DI, as expressed by the branching ratio EC/EC+DI and fragmentation branching ratios (fragment ion production / total ion production) for EC and DI at selected energies for 27-150 keV proton collisions with gas-phase nucleobase molecules.

				Velocity in v 0
		0.5	1.0	1.5	2.0	2.5
		1E-13
	2
	Cross section in cm	1E-14	EC (80 keV) DI (80 keV) Total Ionization (80 keV) Normalized EC *
		1E-15	Fitted Normalized EC Fitted Normalized DI
			Fitted Normalized Total Ionization (EC+DI)
		25		50	75	100 125 150
				Energy in keV

Table 2 :

 2 Absolute cross sections of electron capture, direct ionization, and total ionization in 80 keV proton collisions with gas-phase cytosine, uracil, thymine, and adenine.

	Cross section (10 -15 cm	2 )

Dept. Physics and Astronomy, The Open University (OU), Walton hall, Milton Keynes, MK76AA, UK

Université Hassan II-Mohammedia, Faculté des Sciences Ben M'Sik (LPMC), B.P.7955 Ben M'Sik, Casablanca, Morocco

Institut für Ionenphysik und Angewandte Physik, Leopold Franzens Universitat, Technikerstrasse 25, A-6020 Innsbruck, Austria

Acknowledgements.

The Institut de Physique Nucléaire de Lyon is part of IN2P3-CNRS, the French national research institute for nuclear and particle Physics. Financial support was provided by the French, Austrian, and Moroccan governments and the EU Commission (Brussels), through the Amadeus program, the PICS CNRS 2290 and the CNRS-CNRST convention n°17689. S. Eden acknowledges the FP6 Marie Curie Fellowship (IEF RADAM-BIOCLUS).


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THÈSE D'EXERCICE pour le

A mes parents Françoise et Jean-Bernard, pour leur soutien tout au long de ces années d'études ainsi qu'au reste de ma famille avec une pensée particulière pour mon frère Arnaud et sa femme Aude, ainsi que ma grand-mère qui aura toujours veillé à ce que je ne manque de rien.

A mes amis d'enfance et tout particulièrement Clémentine avec qui j'ai grandi et chez qui j'ai toujours trouvé une porte ouverte pour m'héberger lors de mes cours, Anne-Eloïse qui est à mes côté depuis 26ans, Lucie qui m'a accompagnée lors de mes premiers périples autour du monde et Alexis avec qui j'ai passé de nombreuses soirées étoilées.

A tous mes amis rencontrés en médecine et notamment Juliette et Chloé qui ont été là depuis mes "premiers pas en tant que bébé médecin", Jérémy qui a rendu les TP de biophysique inoubliables, Pauline et Guillaume avec lesquels j'ai partagé beaucoup d'heures de sport, de pâtisseries et de voyages; A toutes mes rencontres bordelaises et tout particulièrement Clémence qui m'a permis de réaliser un inter-CHU mémorable. Une pensée également pour mes co-internes, notamment Hortense et Audrey qui sont devenues de véritables amies. Et je n'oublie pas Antoine pour qui j'ai une pensée particulière.

Merci à l'ensemble des équipes de stage pour votre accueil, votre partage de connaissance : le service de MPR à Clémentel, l'AIA, l'UGECAM, la MSA, l'AIST, le service de dermatologie à Merci pour votre enseignement pendant ces 4 années d'internat mais aussi, je vous remercie sincèrement pour votre soutien, que ce soit lors de mes stages ou de mes démarches professionnelles.

Je vous remercie également pour votre aide dans la réalisation de cette thèse et de la publication à venir.

Monsieur le Professeur Georges BROUSSE Professeur des Universités -Praticien Hospitalier

Psychiatrie et Addictologie, CHU de Clermont-Ferrand

Nous vous sommes reconnaissants d'avoir accepté de faire partie de ce jury de thèse et de nous faire l'honneur de juger notre travail. Soyez assuré de notre gratitude et de notre respect.

A Madame le Docteur Marie-Christine FERRIER LE BOUEDEC, Dermatologue, CHU de Clermont-Ferrand

Nous vous prions de recevoir l'expression de nos sincères et profonds remerciements pour avoir accepté de participer à ce jury de thèse. Soyez également assurée de notre gratitude et de notre respect.

A Madame le Docteur Andrea Daniela Muti, Allergologue et Pneumologue, CHU de Clermont-Ferrand

Nous vous sommes très reconnaissants d'avoir accepté de participer à ce jury de thèse. Je tenais également à vous remercier pour votre partage de connaissances et d'expériences ainsi que pour votre bienveillance envers les internes de votre service.

Introduction

L'eczéma des mains est une maladie chronique fréquente, caractérisée cliniquement par des rougeurs, des vésicules, des desquamations, une infiltration de la peau, des fissures, une hyperkératose et/ou des érosions. [START_REF] Apfelbacher | Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry[END_REF]2 Plusieurs facteurs influencent le pronostic de cette affection inflammatoire de la peau, comme par exemple la notion d'atopie qui représente un des principaux facteurs de risque. [START_REF] Thaci | Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real-world observational study[END_REF][START_REF] Coenraads | Risk for hand eczema in employees with past or present atopic dermatitis[END_REF] Actuellement, les études s'intéressent particulièrement à l'impact des facteurs liés au mode de vie (stress, tabagisme, travail en milieu humide,...) [5][6][START_REF] Sorensen | Associations between lifestyle factors and hand eczema severity: are tobacco smoking, obesity and stress significantly linked to eczema severity? Contact Dermatitis[END_REF] car ils semblent avoir une importance majeure et des mesures préventives peuvent parfois être prises. [START_REF] Soltanipoor | Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A singlecentre, cluster randomized controlled trial[END_REF][START_REF] Gelot | Therapeutic patient education in chronic hand dermatitis[END_REF] De ce fait, différentes classifications existent, basées sur la morphologie ou l'étiologie, mais aucune d'entre elles n'a été universellement acceptée. [START_REF] Lee | Current and emerging therapies for hand eczema[END_REF] Cependant on classe souvent l'eczéma des mains en dermatite de contact irritante, dermatite de contact allergique ou dermatite atopique. [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF] Les autres sous-groupes diagnostiques classiquement utilisés sont la dermite de contact aux protéines, l'eczéma hyperkératosique palmaire et la dyshidrose. [START_REF] Agner | Classification of hand eczema[END_REF] L'European Society of Contact Dermatitis (ESCD) recommande les corticostéroïdes topiques comme traitement de première ligne dans la prise en charge de l'eczéma des mains, [START_REF] Diepgen | Guidelines for diagnosis, prevention and treatment of hand eczema[END_REF] en plus des mesures de prévention, comprenant l'éviction des agents irritants pour la peau et l'utilisation régulière d'émollients. [START_REF] Soltanipoor | Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A singlecentre, cluster randomized controlled trial[END_REF][START_REF] Gelot | Therapeutic patient education in chronic hand dermatitis[END_REF][START_REF] Diepgen | Guidelines for diagnosis, prevention and treatment of hand eczema[END_REF] Mais certains patients sont réfractaires à ce traitement.

L'alitrétinoïne (TOCTINO®) qui a des propriétés anti-inflammatoires et immunomodulatrices [START_REF] Lee | Current and emerging therapies for hand eczema[END_REF][START_REF] Bissonnette | Redefining treatment options in chronic hand eczema (CHE)[END_REF] est alors recommandé comme traitement de deuxième intention depuis fin 2008 en France. L'ESCD a approuvé son utilisation dans le traitement de l'eczéma chronique des mains (CHE) dans les formes sévères ne répondant pas ou insuffisamment aux corticostéroïdes topiques. [START_REF] Diepgen | Guidelines for diagnosis, prevention and treatment of hand eczema[END_REF] Plusieurs essais cliniques ont démontré son efficacité sur les lésions, [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF][START_REF] Kim | Use of alitretinoin in moderate to severe chronic hand eczema: A real-world experience in Korea[END_REF][START_REF] Halioua | Efficacy and safety of oral alitretinoin as treatment for chronic hand eczema in France: a real-life open-label study[END_REF][START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF] avec une amélioration significative de la qualité de vie. [START_REF] Augustin | Impact on quality of life of alitretinoin in severe chronic hand eczema: FUGETTA real-world study[END_REF] Les études évaluant le retentissement sur la qualité de vie mettent en évidence un impact négatif de l'eczéma chronique des mains comparable à celui des autres maladies chroniques

Article

Title page

Effects of alitretinoin on job retention in workers suffering from chronic hand eczema

Cécile Frugier, [START_REF] Apfelbacher | Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry[END_REF] Brigitte Milpied, 2 Catherine Verdun-Esquer, [START_REF] Thaci | Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real-world observational study[END_REF] Brigitte Félix, [START_REF] Coenraads | Risk for hand eczema in employees with past or present atopic dermatitis[END_REF] Jean-François Nicolas, [START_REF] Coenraads | Risk for hand eczema in employees with past or present atopic dermatitis[END_REF] Audrey Nosbaum, 5 Amandine Catelain-Lamy, 6 Marie-Christine Ferrier Le Bouëdec, [START_REF] Sorensen | Associations between lifestyle factors and hand eczema severity: are tobacco smoking, obesity and stress significantly linked to eczema severity? Contact Dermatitis[END_REF] Martine Méharon, [START_REF] Soltanipoor | Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A singlecentre, cluster randomized controlled trial[END_REF] Frédéric Dutheil 9,10

Abstract

Background: Severe chronic hand eczema (CHE) can have a huge negative impact on quality of life, including job loss. For people refractory to dermocorticoids, alitretinoin has already shown positive effects on quality of life but data are scarce on job retention. Therefore, we aimed to assess job retention in workers suffering from CHE.

Methods:

We implemented an open epidemiological, observational, and descriptive study.

We ) and then increased in a very significant way (100% vs 50%, p=0.0)(100% vs 50%, p=)(100% vs 50%, p=0.04). The complete disappearance of eczema was noted in all cases of hyperkeratotic eczema (p<0.05). No significant differences for the other parameters assessed.

Introduction

Hand eczema is a common chronic disease, clinically characterized by redness, vesicles, scaling, infiltration of the skin, fissures, hyperkeratosis, and erosions. [START_REF] Apfelbacher | Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry[END_REF]2 Several factors influence the prognosis of this inflammatory skin condition including an atopic predisposition, which is a major risk factor. [START_REF] Thaci | Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real-world observational study[END_REF][START_REF] Coenraads | Risk for hand eczema in employees with past or present atopic dermatitis[END_REF] Currently, research is focusing on the impact of lifestyle factors (stress, tobacco smoking, wet work, etc.) [5][6][START_REF] Sorensen | Associations between lifestyle factors and hand eczema severity: are tobacco smoking, obesity and stress significantly linked to eczema severity? Contact Dermatitis[END_REF] because they may be of major importance and preventive measures can be taken in some cases. [START_REF] Soltanipoor | Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A singlecentre, cluster randomized controlled trial[END_REF][START_REF] Gelot | Therapeutic patient education in chronic hand dermatitis[END_REF] Thus exist different classifications based on morphology and etiology, however, none of these have been universally accepted. [START_REF] Lee | Current and emerging therapies for hand eczema[END_REF] A classification often used classifies the hand eczema in irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), or atopic dermatitis(AD). [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF] The other diagnostic subgroups classically used are protein contact dermatitis / contact urticaria, hyperkeratotic endogenous eczema and dyshidrotic endogenous eczema. [START_REF] Agner | Classification of hand eczema[END_REF] The European Society of Contact Dermatitis (ESCD) recommends topical corticosteroids as first line treatment in the management of CHE, [START_REF] Diepgen | Guidelines for diagnosis, prevention and treatment of hand eczema[END_REF] in addition with prevention measures including avoiding irritants and using emollient. [START_REF] Soltanipoor | Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A singlecentre, cluster randomized controlled trial[END_REF][START_REF] Gelot | Therapeutic patient education in chronic hand dermatitis[END_REF][START_REF] Diepgen | Guidelines for diagnosis, prevention and treatment of hand eczema[END_REF] But some patients are resistant to this treatment. Alitretinoin which has anti-inflammatory and immunomodulatory properties, [START_REF] Lee | Current and emerging therapies for hand eczema[END_REF][START_REF] Bissonnette | Redefining treatment options in chronic hand eczema (CHE)[END_REF] is then recommended as second-line treatment since the end of 2008 in France. The ESCD approved its use in treating severe and chronic hand eczema (CHE) that does not respond, or responds inadequately, to topical corticosteroids [START_REF] Diepgen | Guidelines for diagnosis, prevention and treatment of hand eczema[END_REF] . Several clinical trials have shown its effectiveness on lesions, [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF][START_REF] Kim | Use of alitretinoin in moderate to severe chronic hand eczema: A real-world experience in Korea[END_REF][START_REF] Halioua | Efficacy and safety of oral alitretinoin as treatment for chronic hand eczema in France: a real-life open-label study[END_REF][START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF] with a significant improvement in the quality of life. [START_REF] Augustin | Impact on quality of life of alitretinoin in severe chronic hand eczema: FUGETTA real-world study[END_REF] In studies evaluating the negative impact on the quality of life, the impact of CHE is comparable to the impact of asthma or psoriasis. [START_REF] Moberg | Hand eczema and quality of life: a population-based study[END_REF] The factors related to occupational exposure have the highest impact with job loss or change at baseline. [START_REF] Cazzaniga | Chronic hand eczema: A prospective analysis of the Swiss CARPE registry focusing on factors associated with clinical and quality of life improvement[END_REF] So, even if change of occupation has a beneficial effect on eczema parameters, it has a negative effect on the quality of life too. [START_REF] Caroe | Job change facilitates healing in a cohort of patients with occupational hand eczema[END_REF] In addition, indirect costs are particularly high in patients with severe CHE. Alitretinoin could reduce this costs in avoiding work losses in employed persons with CHE. [START_REF] Diepgen | Cost-of-illness analysis of patients with chronic hand eczema in routine care in Germany: focus on the impact of occupational disease[END_REF][START_REF] Augustin | Cost-of-illness of patients with chronic hand eczema in routine care: results from a multicentre study in Germany[END_REF] Therefore, the purpose of this study is to estimate the impact of alitretinoin treatment on job retention in workers with CHE.

Methods

Participants

We Technology and Civil Liberties (CNIL). All data were anonymous, and identities were never entered in the database. A human resource creates a number to feed the database (only the first three letters of the hospital where the patient was treated and the initials of the doctor who saw him in consultation will be recorded, followed by a coded number (unique to the study) indicating the order of inclusion of subjects). In no case the names of the persons concerned or their address indicated in clear in the database.

Parameters measured

The primary objective of this article is to study the job retention of workers with CHE treated by alitretinoin or return to the usual workstation if the patient was on a sick leave. To be done, a questionnaire was established in conjunction with dermatologists and occupational physicians in Bordeaux. It focuses on:

Sociodemographics data such as age, gender and education level were collected. In a second step, 3 age groups were created for the statistical analysis: a first group including patients under 30 years, a second including those between 30 and 50 years , and a last group including those over 50 years.

Medical data such as the diagnosis of CHE, the period of treatment with alitretinoin (dosage, tolerance, duration), side effects and relapses when treatment is stopped. A relapse was defined as a new eczema flare-up after stopping treatment. The severity of these relapses was taken into account by asking the patient how they managed this new episode. The effectiveness of alitretinoin treatment was evaluated at the time of the end of the treatment by patients: 3 groups have been created: "healing" if hand eczema had completely disappeared, "improvement" if hand eczema had partially regressed (at least 50%) and judged sufficient by the patient, and "no effect" in the other cases. Regarding the diagnosis of CHE, we classify in ACD when relevant allergy has been found (systematic patch testing), ICD in the absence of a relevant allergy that may explain the eczema but the presence of relevant irritant factors and AD when the patient did not present any of the above criteria and this diagnosis was retained by his dermatologist. When possible, details of the diagnosis of eczema have been identified

as dyshidrotic eczema, hyperkeratotic eczema and the presence of particularly disabling cracks.

Occupationnal data such as occupational situation when the CHE start (workplace, working time, working conditions) and the current occupational status (wether the professional change was related to hand eczema or not). About occupational exposures, it does not exist a universal definition of wet work. We considered the work in a wet environment when workers had to immerse their hands in liquids for more than 2 hours in an 8-h shift, or wearing gloves for more than 2h and/or washing hands more than 20 times per shift because it is the definition most commonly used. [START_REF] Lund | Wet work exposure: comparison of observed and self-reported data[END_REF][START_REF] Flyvholm | OEESC-2005--summing up on the theme irritants and wet work[END_REF][START_REF] Jungbauer | Exposure of the hands to wet work in nurses[END_REF] Life style factor such as hobbies, exposure to particular agents (type of protection used) in particular household chores (quantification of time per week), tobacco smoking during treatment and stress impact assessment.

Methodology of data assessment

A first part of the information was collected using the medical file for more precision such as the nature of the lesions observed, the results of the allergy skin tests, quantity of drug dispensed, prescription dispensation date, prescription duration, the side effects observed or if sick leaves were prescribed. All these data having been verified secondarily with the patient.

In case of discrepancy noted, the patient was excluded from the study.

The questionnaires were initially sent by post. Non-respondents were contacted by phone (data collection using the questionnaire explained by phone following their oral agreement to participate in the study).

Statistics

Considering the hypothesis that the number of patients maintained in employment is 80% and to have a precision of the confidence interval at 95% in the order of ±11%, it was necessary to

Results

Participants

Among the 111 patients identified with CHE and alitretinoin prescription, 53 were included for data on the primary outcome. 17 returned a completed questionnaire, the other 36 were contacted by telephone. Regarding secondary outcomes, 29 provided details on the diagnosis of their eczema, 31 gave information on their smoking status and 35 commented on the possible link between stress and their pathology.

The study flowchart is shown in Figure 1.

Sociodemographic characteristics at baseline : table I

Overall, 34 (64.2%) of the patients included in the study were male. Their mean age at which lesions appear was 43 ± 13.

Job retention data: table I

Among the 53 workers included in the study, 44 (83%) kept their job (p<0.001) including 3

(5.7%) workers who benefited a workstation layout. 5 (9.4%) were forced to change profession and therefore 4 (7.5%) other stopped working because of CHE: 2 patients not responding to treatment and the 2 others relapsed quickly after the end of the treatment and failed to control new relapses.

In addition, there is a decrease in the rate of sick leave with 38% of stoppage before treatment by alitretinoin compared to 17% during treatment and only 7.6% after treatment (p=0.005);

After treatment, 2 patients belong to the improvement group and 2 others to the no effect group (p=0.048).

Data on treatment efficiency based on socio-demographic data

23 (43.4%) patients observed a complete disappearance of lesions, 23 (43.4%) an significantly improvment of their lesions and in 7 patients, alitretinoin treatment was not effective.

Among the 7 patients who did not respond to treatment, 60% were over 50 years of age (n=4; p=0.019) and 86% had a bachelor's degree or less (n=6; p=0.009). The overall data collected did not show any significant correlations for the other parameters although men tend to be more improved by treatment (about 91% efficacy in men compared to 79% in women; Table I). The majority of people worked full-time (n=50; 94.3%), which does not allow us to study a difference in the effect of treatment according to working time.

Differences in treatment effectiveness according to diagnosis

In ACD, we observed a tendency to achieve complete healing (53.8%, n=7 II). This relapse rate is relatively stable over time up to 24 months of treatment (about 50% relapse) but beyond 24 months, a 100% relapse rate is observed (p=0.04; Figure 2).

The treatment has relatively the same efficacy in patients with or without allergy (about 43% are cured, 43% are improved and 14% have no effect). However, the cure rate tends to be higher in patients with a relevant allergy (58% compared to 17% when the allergy is irrelevant and 44% in patients without allergies) or in cases allergies at least partly occupational (the complete healing rate is 67% compared to 48% in other cases; Table I).

Overall, we obtain an equivalent percentage of improvement and cure rate during the first 6 months of treatment, then the patients treated between 6 and 24 months only obtain an improvement. Beyond 24 months, the total healing of eczema does not last over time (Figure 2).

Tobacco and stress interference

Tobacco does not cause any significant difference in effects of alitretinoin with an efficacy of 92.3% for smokers and 83.3% for non-smokers. There is no difference either on job retention.

However, there is a trend towards an increase relapse rate among smokers, although this is still not significant (75.0% relapse in the smokers' group compared to 57.1% in the nonsmokers' group; Table III).

Stress does not lead to any significant difference in the effects of treatment (effectiveness in 93.7% of patients reporting a link between their lesions and stress compared to 89.5% in other patients). No significant difference either on the percentage of relapse (66.7% in the stress group compared to 56.2% in the other group) or on the job retention (12% compared to10% respectively; Table IV).

Discussion

The main findings of this study are the job retention of people with severe CHE who are resistant to local corticosteroids and treated with alitretinoin and the reduction in sick leaves, despite the presence of known aggravating factors of the disease such as stress and smoking.

This treatment must be combined with the usual preventive measures that remain essential.

Data on job retention

The main objective of this study was to assess the impact of alitretinoin in patients with CHE refractory to topical corticosteroids. The vast majority of participants (n=49; 92.5%) maintained the ability to work, whether at the same workstation or another: 44 (83%) were able to keep their job (p<0.001) including 3 (5.7%) people with a workstation layout, 5 (9.4%) changed workstation because of their CHE and 4 (7.5%) were forced to stop working because of their CHE. Our results are difficult to compare with other studies since none of them have specifically examined the conditions of job retention in these patients. However, Thaci et al. [START_REF] Thaci | Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real-world observational study[END_REF] described 12.4% workers were incapable of work due to CHE before alitretinoin treatment compared to 2.2% after treatment. This slight difference between these results and ours can be explained by the difference between our 2 studies in the percentage of patients with hyperkeratosic eczema. Indeed, alitretinoin is particularly effective in hyperkeratotic eczema [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF][START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF][START_REF] Smith | Treatment of severe, chronic hand eczema: results from a UK-wide survey[END_REF] and 61.2% of the patients followed in the Thaci et al. study had this form of eczema compared to only 13.2% in our study. Furthermore, 37.7% of workers were in sick leave due to CHE before treatment with alitretinoin, 17% during treatment and 7.6% after treatment (p=0.005). This means that the number of patients who need sick leave is 5 times lower after alitretinoin treatment, knowing that the people who still need sick leave are only those who not had an effect with the treatment or only partially. So in addition to having a positive effect on job retention, the treatment may lead to cost savings by preventing professional retraining. Indeed, CHE is reported to reduce work productivity, increase the number of work days missed and markedly increase medical costs. [START_REF] Diepgen | Cost-of-illness analysis of patients with chronic hand eczema in routine care in Germany: focus on the impact of occupational disease[END_REF][START_REF] Augustin | Cost-of-illness of patients with chronic hand eczema in routine care: results from a multicentre study in Germany[END_REF] These results are in accordance with previous studies, [START_REF] Thaci | Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real-world observational study[END_REF][START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF] which showed a trend for a reduction in the level of sickness absence during alitretinoin treatment.

These results provide evidence that alitretinoin can reduce work incapacity.

Other data related to employment

Despite the absence of significant results concerning the other parameters related to employment (professional status, occupational sector, employment contract and working time), it can be seen that the mechanics, farmers, craftsmen and metal workers seem to be a higher risk of developing CHE because they represent 49.1% of the patients in our study (39.6% belonging to the industrial and agricultural activities group). Metal workers and mechanics are known to be among the high-risk professions of developing CHE. [START_REF] Apfelbacher | Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry[END_REF][START_REF] Wilke | Interdisciplinary and multiprofessional outpatient secondary individual prevention of work-related skin diseases in the metalworking industry: 1-year follow-up of a patient cohort[END_REF] The most common occupational exposures in our study were wet work (37%), chemicals including among others oils, solvents, paintings and soaps (33%) and metals (16%), with only 21% of patients reporting no specific exposure and 51% reporting at least 3 different types of exposure (corresponding to 27 people). Wet work non-occupational exposure was also taken into account in the study but was not found in any of the patients. The association CHE with hand washing and use of gloves is known. 6 Many occupational groups including healthcareworkers, food handlers, hairdressers, metal workers and construction workers are known to be exposed to wet work. Furthermore, in most cases, wet work exposure is accompanied by detergents and cleansers, which in turn may aggravate the adverse effects of exposure. [START_REF] Behroozy | Wet-work Exposure: A Main Risk Factor for Occupational Hand Dermatitis[END_REF] However, it is interesting to note that even minor changes in exposure to wet work were associated with improvement and healing. [START_REF] Caroe | Hand eczema and wet work: doseresponse relationship and effect of leaving the profession[END_REF] In our study, the data for this wet work are declarative data collected during the telephone call. It exists a noticeable misclassification between the estimations and the observations on all wet work variables, but largest for total wet work. [START_REF] Lund | Wet work exposure: comparison of observed and self-reported data[END_REF] So our data can be overestimated or underestimated.

Although glove use is a known risk factor for developing ACD or ICD, [START_REF] Bensefa-Colas | Occupational allergic contact dermatitis and major allergens in France: temporal trends for the period 2001-2010[END_REF] it is its misuse and association with other risk factors such as excessive hand washing or additionnal hazardous substances that leads to the accumulation of barrier damage and injuries. [START_REF] Weistenhofer | Protection during production: Problems due to prevention? Nail and skin condition after prolonged wearing of occlusive gloves[END_REF][START_REF] Weistenhofer | Occlusive gloves and skin conditions: is there a problem? Results of a cross-sectional study in a semiconductor company[END_REF] Indeed, it is used in preventive measures when using irritants for example, but always in combination with a therapeutic education program. Therapeutic education is an efficient way to help patients to adopt skin protection measures essential to healing. [START_REF] Gelot | Therapeutic patient education in chronic hand dermatitis[END_REF] Although all the studies doesn't show a significant effect, they showed overall positive effects. [START_REF] Soltanipoor | Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A singlecentre, cluster randomized controlled trial[END_REF] It's significantly improving the participants' knowledge and inducing significant behavioral changes. [START_REF] Gasparini | A pilot study for the prevention of chronic hand eczema in healthcare workers of an Italian University Hospital[END_REF] A study by Wilke et al.

examining the impact of preventive measures in a metalworking industry demonstrated that the comprehensive prevention program positively influences the course of work-related skin diseases, increase the possibility to continue working in a "high-risk" profession and improves the disease management of metal workers. [START_REF] Wilke | Interdisciplinary and multiprofessional outpatient secondary individual prevention of work-related skin diseases in the metalworking industry: 1-year follow-up of a patient cohort[END_REF] So occupational skin diseases are common diseases with a huge potential for prevention. The existing knowledge justifies the relevance of reducing exposure and introducing prevention programmes. [START_REF] Flyvholm | OEESC-2005--summing up on the theme irritants and wet work[END_REF] The impact of preventive measures was not taken account in our study because they were systematically associated in our study, as recommended in the updated guideline. [START_REF] Fartasch | S1 guideline on occupational skin products: protective creams, skin cleansers, skin care products (ICD 10: L23, L24)--short version[END_REF] But these measures seem essential for the effectiveness of the treatment and also to avoid relapses.

Indeed, 12 patients specified that relapses occurred when they no longer performed preventive measures. These patients were able to control their eczema with the rapid use of local corticosteroids and the reintroduction of preventive measures (moisturizers and wearing gloves during household chores were the 2 most frequently mentioned).

Coexisting non-occupational risk behaviors are just as important in the prevention [START_REF] Gasparini | A pilot study for the prevention of chronic hand eczema in healthcare workers of an Italian University Hospital[END_REF] and were well considered in our study: 9 (17%) patients had leisure-time exposure, 4 (7.5%) of them had a relevant allergy.

Data on CHE

Treatment was effective in 46 (86.8%) of patients, with complete disappearance of lesions in 23 (43.4)% of them and a significant improvement in other cases. It is difficult to compare our results with other studies because it exists a considerable heterogeneity of measurement instruments in hand eczema, so the outcome measurements are not harmonize and it considerably limits the comparability in the study results. [START_REF] Ronsch | Which outcomes have been measured in hand eczema trials? A systematic review[END_REF] Indeed, we can consider the effectiveness of the treatment in our study ranging from 43.4% (totally cured) to 86.8%

(patients who have noticed an significant improvement). These data appear to match with what has been found in other studies, let it be in studies that included a similar population (44% in the study by Kwon et al. 11 ; 62% in the study by Kim et al. [START_REF] Kim | Use of alitretinoin in moderate to severe chronic hand eczema: A real-world experience in Korea[END_REF] ) or in those with a larger number of patients included (41% in the study by Halioua 16 ; 48% in the study by Augustin 18 ; 57% in the Diepgen et al.'s study [START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF] ; 53% in Ruzicka et al.'s study [START_REF] Ruzicka | 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[END_REF] ). Finally, Veien et al. [START_REF] Veien | Hand eczema: causes, course, and prognosis II[END_REF] finds results similar to ours (86% improvement with 43% relapse). The slightly better therapeutic response in our study might be explained by the fact that patients were able to continue with some concomitant topical corticosteroids.

The duration of treatment was very variable in our study (in month: 53±12.2). The effectiveness was evaluated at the end of 3 months after the prescription with a stop for people who showed no improvement and generally a continuation of the treatment for an additional 3 months for the others. Some dermatologists reduced doses from 30mg to 10mg before stopping, others did not. 62% of patients received treatment for 6 months or less (classic duration), 21% between 6 months and 1 year, and 11% for 2 years or more. It can be seen that the first 6 months have resulted in an equivalent rate of complete recovery and improvement, while there is a tendency to achieve more improvement with continued treatment up to 2 years. The relapse rate after stopping treatment is about 50% over this 2 years period. So people who respond to treatment seem to be responding quickly. This notion of efficacy from 3 months to 6 months has already been demonstrated in many studies as the Schmith et al.'s study [START_REF] Schmith | Use of Longitudinal Dose-Response Modeling to Support the Efficacy and Tolerability of Alitretinoin in Severe Refractory Chronic Hand Eczema (CHE)[END_REF] or the Kwon et al.'s study. [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF] On the other hand, patients treated for 2 years or more have resulted in a total disappearance of lesions but there is a relapse in 100% of cases. This increase in the relapse rate questions about the usefulness of continuing treatment in the long term compared to earlier therapeutic change. Especially since the percentage of patients not being able to put treatment recommendations into practice increased over time. [START_REF] Apfelbacher | Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry[END_REF] Compared to previous trials, the relapse in our study was most frequent. [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF][START_REF] Ruzicka | 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[END_REF] This may be because our patients underwent follow-up assessment at longer intervals. The duration between the end of the treatment and the investigation was on average 37±23 months.

Concerning the different forms of eczema, our study agrees with a particular efficacy of alitretinoin in hyperkeratotic forms [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF][START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF][START_REF] Smith | Treatment of severe, chronic hand eczema: results from a UK-wide survey[END_REF] even if the results are not significant ( 7hyperkeratotic forms all improved or cured by treatment). There is also no significant difference in effectiveness between AD, ACD and ICD. Moreover, having a professional allergy does not seem to have an impact on treatment, however, we observe that the presence of an identified and relevant allergy leads to a cure more often (58%) than the others (39%). This is due to the possibility of removing the allergen responsible for eczema from the hands, which facilitates complete healing.

Regarding age, among the 7 patients who did not respond to treatment, 4 are over 50 years old (representing 57% of non-responders). Some studies identified a worse prognosis in elderly men [START_REF] Sorensen | Associations between lifestyle factors and hand eczema severity: are tobacco smoking, obesity and stress significantly linked to eczema severity? Contact Dermatitis[END_REF][START_REF] Cvetkovski | Prognosis of occupational hand eczema: a follow-up study[END_REF] which may explain the trend in these results. Indeed, we can suppose that eczema often has an older course and the reconstruction of the skin barrier is more difficult with age.

22 (41.5%) of patients reported side effects, most of which disappeared after a few months or when the dose of treatment was reduced (from 30mg to 10mg), which had already been reported in the studies. [START_REF] Apfelbacher | Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry[END_REF] These side effects have also been responsible for the early discontinuation of treatment in some patients despite its effectiveness (7 patients reported stopping as soon as they felt the improvement was sufficient due to side effects). Headaches were the most common with 53% of this patients reporting them, followed by biological abnormalities and skin side effects (facial flushing, desquamation) with 27%, asthenia and severe anxiety at 13% and 7% respectively. It should be noted that 4 patients reported 2 side effects. These side effects are well known, especially the headaches that are most frequently reported, [START_REF] Christoffers | Interventions for hand eczema[END_REF] the others having also already been reported in the study by Vrignaud et al. (study focusing on new adverse effects (not listed) of alitretinoin). 43

Data on tobacco and stress

In this study, the effect of stress and tobacco on treatment did not show significant results.

The treatment seems to have a comparable effect on smokers or not (92.3% and 83.3% who have noticed an effect of the treatment respectively) and on patients who report or not an influence of stress in their pathology (93.7% and 89.5% respectively), without any effect on job retention either. However, a trend towards an increase in the relapse rate in both groups, more marked among smokers (75.0% among smokers compared to 57.1% among non smokers; 66.7% among patients who report an influence of stress compared to 56.2% among those not reporting a link). But our 10 years retrospective study did not allow us to take into account this data satisfactorily (a lot of data is missing; no quantification possible; no precise evaluation with the chronology of relapses) this is why all patients did not answer these questions (only about thirty patients), and a well conducted complementary study with a larger population would be interesting to conduct. Indeed, no studies on the efficacy of alitretinoin have taken into account these 2 factors despite the effects they are well known in the pathology. [START_REF] Sorensen | Associations between lifestyle factors and hand eczema severity: are tobacco smoking, obesity and stress significantly linked to eczema severity? Contact Dermatitis[END_REF][START_REF] Sorensen | Tobacco smoking and hand eczema -is there an association? Contact Dermatitis[END_REF] Olesen et al. 5 have recently focused on the factors influencing prognosis for occupational CHE and they highlighted that tobacco smoking and stress are factors associated with the persistence of eczema, which could explain the higher number of relapses among smokers and people exposed to stress. So improve smoking habits of patients and their psychological well-being represent a promising strategy to improve the prognosis of CHE in the future. 5

Limitations

The main limitation of this study is the absence of a control group not receiving alitretinoin.

However the design of this study was observational and all patients with an indication of treatment received alitretinoin. This could have provided a more interesting level of evidence to our study, but it was not ethically acceptable to propose an interventional study with a population not treated or with placebo, thus representing a loss of opportunity for patients.

Indeed, the effectiveness of alitretinoin has already been demonstrated in many studies [START_REF] Kim | Use of alitretinoin in moderate to severe chronic hand eczema: A real-world experience in Korea[END_REF][START_REF] Halioua | Efficacy and safety of oral alitretinoin as treatment for chronic hand eczema in France: a real-life open-label study[END_REF][START_REF] Diepgen | Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients[END_REF] and in particular in studies with a placebo group. [START_REF] Ruzicka | 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[END_REF][START_REF] Christoffers | Interventions for hand eczema[END_REF][START_REF] Fowler | A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of alitretinoin (BAL4079) in the treatment of severe chronic hand eczema refractory to potent topical corticosteroid therapy[END_REF] Time constraints did not allow us to establish a clinical study comparing two populations with two different treatments. This could have been interesting especially with a similar population treated with methotrexate since it is the treatment that appears to be effective in patients who do not respond to alitretinoin.

However, the main objective of our study was not to show the superiority of this treatment over others but its impact on job retention. Of the 109 patients initially enrolled in the study, only 53 were included, representing a small population. But this has resulted in harmonized data regarding the main objective of the study and this population has the advantage of being multicentric. In addition, several studies have a number of participants similar to ours. [START_REF] Kwon | Efficacy and Safety of Alitretinoin for Chronic Hand Eczema in Korean Patients[END_REF][START_REF] Kim | Use of alitretinoin in moderate to severe chronic hand eczema: A real-world experience in Korea[END_REF] The classification concerning the diagnosis can be discussed, patients could have an ACD and an AD. In this case, the patients were classified in the ACD group. But we have performed analyses taking into account atopy to try to evaluate the influence of this factor. The evaluation of the effectiveness can also be discussed. In the absence of harmonized measures, [START_REF] Ronsch | Which outcomes have been measured in hand eczema trials? A systematic review[END_REF] we chose the system that we thought was easiest for the patient to understand in order to have representative data. The evaluation of the duration of sick leaves could not be optimal, they could have been initiated and/or prolonged by other health professionals. So it wasn't taken into account in our study. The presence of interfering factors was taken into account as much as possible according to the data in the current literature, 5 but these data were not always informed and could not be evaluated satisfactorily, particularly the assessment of stress due to the retrospective nature of the study. However, this is the first study on alitretinoin that takes into account these factors. Finally, in this retrospective study there is a difference in the distance from the end of treatment according to the patients. The mean duration between the last time the alitretonoin was taken and the investigations was 37±23 months which seems to be a reasonable hindsight.

Conclusion

Alitretinoin has a positive impact on job retention in patients with severe and CHE refractory to topical corticosteroids: it reduces the number of days of sick leave and allows the same workstation to be maintained in most cases. It can be observed that this treatment improves eczema lesions or even completely disappears, but the relapse rate of this chronic pathology in the long term remains high. Therefore, the usual preventive measures should be continued after treatment, and should be combined if necessary with specific measures, particularly at the workplace (consider job accommodation to promote job retention). Lifestyle factors such as tobacco and non-occupational exposures must also be taken into account.

Conclusion

  Bordeaux, le CPP et la MTPH, le service de pneumologie et l'équipe du Dr Jouaville. Merci pour votre accueil et votre accompagnement. Ce fut à chaque fois une expérience enrichissante tant sur le plan professionnel que personnel. Pour terminer, je voulais remercier les personnes ayant permis à la réalisation de cette thèse: Dr Milpied, Dr Méharon, Dr Ferrier Le Bouedec, Dr Nosbaum, Dr Catelain-Lamy, Pr Nicolas et le Pr Frédéric Dutheil.

  conducted an epidemiological, observational, descriptive, open-label, non-comparative and multi-center study for which we sent self-questionnaires to the patients treated for CHE in the dermatology department of Bordeaux, Lyon, Grenoble and Clermont-Ferrand between July 2009 and June 2019. Some patients were contacted by phone. They had to be employed, working or on sick leave at the time of the first consultation. They must have been treated with alitretinoin during their medical management. Exclusion criteria were patients retired, unemployed, with an other interfering skin pathology (psoriasis or other severe or acute dermatological conditions that interfere with the diagnosis of CHE), answering with an incomplete questionnaire, taking drugs that may interfere with the study results (only topical corticosteroids are allowed), with comprehension difficulties or who did not took the treatment as prescribed. This observational study received approval from the Ethics Committee of the University Hospital of Clermont-Ferrand, France, and from National Commission for Information

  2 years (median 46 years; extremes 17-64 years). In the end, 25 patients were recruited by the Bordeaux, 18 by the Lyon, 3 by the Grenoble and 7 by the Clermont-Ferrand. Concerning their occupation, they have been classified into 4 groups in which occupational exposures are equivalent. Mechanics, farmers, craftsmen and metal workers were the most represented along the health and cleaning occupations (respectively 49.1% and 18.9%

L

  'alitrétinoïne a un impact positif sur le maintien dans l'emploi des patients atteints d'eczéma chronique sévère des mains, réfractaire au traitement de première intention par corticostéroïdes topiques. Il permet dans la plupart des cas le maintien au même poste de travail ainsi que la diminution du nombre de jours d'arrêt de travail.On observe que ce traitement aboutit à l'amélioration des lésions d'eczéma voire à leur complète disparition mais le taux de rechute à long terme de cette pathologie chronique reste important. Par conséquent, les mesures de prévention habituelles doivent être poursuivies après le traitement, et doivent être associées si besoin à des mesures spécifiques, notamment sur le lieu de travail (penser à l'aménagement de poste afin de favoriser le maintien dans l'emploi). Les facteurs liés au mode de vie comme la consommation de tabac et les expositions non professionnelles doivent être également pris en compte.

5 . 2 . 2 Fig. 2 .☐☐☐ Bac +2 ou 3 ☐☐☐

 52223 Effect of the treatment over time ……………………………………………….………………………………………………………....... Raison(s) de l'arrêt du traitement par alitrétinoïne = TOCTINO : ☐ Guérison (disparition complète et totale des lésions) Amélioration suffisante de vos lésions (disparition d'au-moins 50% de vos lésions avec absence de gêne pour vos activités au quotidien) ☐ Absence d'efficacité ☐ Mauvaise tolérance (ayant conduit à l'arrêt) ☐ Autre : ……………………………………………………………………………………………........ Avez-vous eu une récidive de vos lésions (apparition de nouveau d'eczéma au niveau de vos mains) après l'arrêt du traitement par alitrétinoïne = TOCTINO ? ☐ Oui ☐ Non ☐ Vous ne savez pas Précisions éventuelles : ………………………………………………………………………………...... Si vous avez constaté une récidive de vos lésions, comment l'avez-vous prise en charge? ☐ Mesures de protection de vos mains (port de gants, crèmes hydratantes / émolients) Traitement local par crèmes corticoïdes ☐ Reprise du traitement par alitrétinoïne = TOCTINO ☐ Autre traitement; précisez: ................................................................................................................. Précisions éventuelles : ………………………………………………………………………………...... Fumiez-vous au moment du traitement par alitretinoïne = TOCTINO ? ☐ Oui ☐ Non ☐ Vous ne savez pas Précisions éventuelles : ………………………………………………………………………………...... De manière générale, avez-vous constaté un effet du stress sur votre eczéma (apparition d'une nouvelle poussée, aggravation de l'eczéma) ? ☐ Oui, lien évident entre votre état de stress et votre eczéma ☐ Oui, le stress peut expliquer parfois une aggravation des lésions ☐ Non, aucun lien établi ☐ Vous ne savez pas Précisions éventuelles : ………………………………………………………………………………...... NIVEAU D'ETUDE / DERNIER DIPLOME OBTENU: ☐ 2 ème ou 3 ème cycle ou grandes écoles Bac général, précisez………………………………………………………. Bac technique ou professionnel, précisez……………………………….. ☐ CAP/BEP, précisez…………………………………………………………. Brevet des collèges ☐ Sans diplôme ☐ Autres : précisez……………………………………………………………. POSTE DE TRAVAIL AU MOMENT DE L'ECZEMA : Nom de l'entreprise/ Domaine d'activité : ……………………………………………………………. Intitulé de votre poste de travail : …………………………………………….………......................... Statut professionnel : ☐Salarié(e) ☐Indépendant(e) ☐Employeur ☐Apprenti(e) ☐Étudiant(e) Précisions éventuelles : ………………………………………………………………………………...... Type de contrat de travail : ☐CDI ☐CDD ☐Intérim ☐Autres : ………………………........... Temps de travail : ☐ Temps complet ☐ Temps partiel; précisez: ............ ☐ Vous ne savez pas Précisions éventuelles : ………………………………………………………………………………...... Quels sont les produits que vous manipuliez au moment de l'apparition de l'eczéma des mains ? …………………………………………………………………………………………………………… ……………………………………………..................................………….............................................. Quels outils/machines utilisiez-vous dans le cadre de votre travail au moment de l'apparition de l'eczéma des mains ? …………………………………………………………………………………………………………… ……………………………………………....…………..................................………….......................... Au travail, quels équipements de protection portiez-vous au moment de l'apparition de l'eczéma ? Si port de gants, précisez la matière/le type: ……………………………………………………………………............................................................

Table des matières

 des

Remerciements....................................................................................................................................... Limitations ..................................................................................................................... 2.7 Conclusion ............................................................................................................................. 3. Conclusion ..................................................................................................................................... 4. References ..................................................................................................................................... 5. Annexes. ........................................................................................................................................ 5.1 Tables .................................................................................................................................... 5.1.1 Table I. Main results ...................................................................................................... 5.1.2 Table II. Relapse rate according to diagnosis .............................................................. 5.1.3 Table III. Tobacco data ................................................................................................ 5.1.4 Table IV. Stress data ..................................................................................................... 5.1.5

Table V .

 V Side effects .................................................................................................... 5.2 Figures ................................................................................................................................... 5.2.1 Fig.1. Flow-chart and study design ............................................................................... 5.2.2 Fig.2. Effect of the treatment over time......................................................................... 5.3 Questionnaire ......................................................................................................................... 6. Serment d'Hippocrate ....................................................................................................................

	Liste des abréviations
	ACD: Allergic Contact Dermatitis
	AD: Atopic Dermatitis
	CHE: Chronic Hand Eczema
	ESCD: European Society of Contact Dermatitis

ICD: Irritant Contact Dermatitis

OD: Occupational Disease

  include at least 51 patients. All patients for whom data were available were included in the analyses. All parameters are represented descriptively. Statistical analyses were performed using Stata software (version 13, StataCorp, College Station, United States). Participants'

	characteristics were expressed as mean ± standard-deviation (SD) or median [interquartile
	range] for continuous data (assumption of normality assessed by using the Shapiro-Wilk test)
	and as numbers and associated percentages for categorical parameters. The comparisons
	between groups were carried out using the Chi-squared or Fischer's exact test for categorical
	variables. A p-value <0.05 was considered statistically significant. Missing values for the

parameters evaluated secondarily such as the details of the diagnosis (hyperkeratotic, dyshidrotic and cracks), tobacco smoking during treatment and stress impact assessment, were excluded separately for each analysis. The evaluation of the efficacy of alitretinoin is based on the observation of the patient at the end of treatment, all patients were not seen in consultation in this time (concordance verification using their medical records; no discrepancies were observed in this study). Finally, quantitative variables were compared between independent groups by ANOVA or Kruskal-Wallis test if ANOVA conditions were not met (normality and homoscedasticity analyzed using the Bartlett test). When appropriate, post-hoc tests were performed considering multiple comparisons (Tukey-Kramer post ANOVA and Dunn after Kruskal-Wallis). The comparisons between groups were carried out using the Chi-squared or Fischer's exact test for categorical variables. When appropriate, a post-hoc test was used (Marascuillo procedure).

  ). Treatment efficacy is noted in all cases of hyperkeratotic eczema, compared to dyshidrosic and fissure

	forms.
	26 (49.1%) patients observed one or more relapses after stopping the treatment including 19
	(35.8%) patients who required local (corticoids, tacrolimus) or systemic treatment
	(methotrexate, acitretine; Table

5. Annexes. 5.1 Tables 5.1.1 Table I. Main results

	5.1.	Sample size Sample size Sample size Sample size	Healing Healing Healing Healing	Improvement Improvement Improvement Improvement	No effect No effect No effect No effect	P-value P-value P-value P-value
		N = 53 (100%) N = 53 (100%) N = 53 (100%) N = 53 (100%)	N = 23 (100%) N = 23 (100%) N = (100%) N = 23 (100%) N = 23 (100%) N = (100%) N = 23 (100%) N = 23 (100%) N = (100%) N = 23 (100%) N = 23 (100%) N = 7 (100%)
	Occupational allergy Occupational sector Wood dust Change of job due to eczema
	Yes No In part Industrial and agriculture activities Trade and finance activities Yes No Yes No Hospital and scientific activities Leisure-time exposure Job lost due to eczema	6 (11.3) 9 (17.0) 3 (5.7) 21 (39.6) 8 (15.1) 4 (7.6) 49 (92.4) 5 (9.4) 48 (90.6) 9 (17.0)	4 (17.4) 6 (26.1) 2 (8.7) 14 (60.9) 1 (4.3) 1 (4.4) 22 (95.6) 1 (4.4) 22 (95.6) 4 (17.4)	1 (4.4) 2 (8.7) 0 (0) 6 (26.1) 6 (26.1) 3 (13.0) 20 (87.0) 4 (17.4) 19 (82.6) 3 (13.0)	(14.3) (14.3) (14.3) (14.3) (14.3) (0) (100) 0 (0) 7 (100) (28.6)	0.781 0.333 0.064
	Doubt No allergy Administrative and teaching activities Working time Yes No Yes No	Sample size 1 (1.9) 34 (64.1) 15 (28.3) 9 (17.0) 44 (83.0) 4 (7.5) 49 (92.5)	Healing 0 (0) 15 (65.2) 4 (17.4) 4 (17.4) 19 (82.6) 2 (8.7) 21 (91.3)	Improvement 1 (4.4) 15 (65.2) 8 (34.8) 4 (17.4) 19 (82.6) 0 (0) 23 (100)	No effect (0) (57.14) (42.8) (14.3) (85.7) 2 (28.6) 5 (71.4)	P-value 1.000 0.042
	Demographics Sex Man Woman Age <30 years 30-50 years >50 years Education level Bachelor degree or less Undergraduated Master degree Diagnostic Atopic demartitis Allergic contact dermatitis Irritant contact dermatitis Allergy relevance Yes Non Doubt No allergy Yes No Yes No Workstation layout Occupational characteristics Professional roles Administrative profession Mechanics, farmers, craftsmen and metal workers Food and catering workers Yes No Food products Yes No Same profession Health and cleaning profession Water contact** Professional status after the treatment Yes No Yes No Glove wearing more than 2h After alitretinoin treatment CHE No Not concerned Too short follow-up Yes No Yes No Metals During alitretinoin treatment ≥24 months Relapse after stopping treatment Yes Yes No Yes No Chemical products Before Alitretinoin treatment Eczema aggravated with work Yes No No idea Duration of treatment ≤6 months 7 to 12 months 13 to 18 months Full-time Cumulative number of professional Recognition of handicapped worker status Part-time Occupational exposures Number of professional exposures 0 1 2 3 Sick leaves exposures (chemicals, metals, glove, water, food, wood) 0 Yes No 1 Occupational disease 2 3 Yes No	N = 53 (100%) 34 (64.2) 19 (35.8) 13 (24.5) 18 (34.0) 22 (41.5) 16 (30.2) 33 (62.3) 4 (7.5) 3 (5.7) 13 (24.5) 37 (69.8) 12 (22.6) 6 (11.3) 1 (1.9) 34 (64.2) 4 (7.6) 49 (92.4) 3 (5.7) 50 (94.3) 11 (20.7) 26 (49.1) 6 (11.3) 10 (18.9) 43 (81.1) 44 (83.0) 9 (17.0) 10 (18.9) 32 (60.4) 21 (39.6) 4 (7.6) 49 (92.4) 19 (35.8) 7 (13.2) 1 (1.9) 19 (35.8) 34 (64.2) 9 (17.0) 44 (83.0) 6 (11.3) 26 (49.1) 38 (71.7) 15 (28.3) 20 (37.7) 33 (62.3) 36 (67.9) 14 (26.4) 3 (5.7) 31 (58.5) 13 (24.5) 3 (5.7) 50 (94.3) 3 (5.7) 11 (20.8) 5 (9.4) 10 (18.9) 27 (50.9) 11 (20.8) 2 (3.8) 51 (96.2) 5 (9.4) 10 (18.9) 27 (50.9) 5 (9.4) 48 (90.6)	N = 23 (100%) N = 23 (100%) N = (100%) 17 (73.9) 14 (60.9) (42.9) 6 (26.1) 9 (39.1) (57.1) 9 (39.1) 2 (8.7) (28.6) 4 (17.4) 13 (56.5) 10 (43.5) 8 (34.8) (57.1) 4 (17.4) 6 (26.1) 18 (78.3) 14 (60.9) (14.3) 1 (4.3) 3 (13.0) (0) 1 (4.4) 2 (8.7) (0) 7 (30.4) 4 (17.4) (28.6) 15 (65.2) 17 (73.9) (71.4) 7 (30.4) 3 (13.0) (28.6) 1 (4.4) 4 (17.4) 0 (0) 1 (4.4) (0) 15 (65.2) 15 (65.2) (57.1) 2 (8.7) 2 (8.7) (0) 21 (91.3) 21 (91.3) (100) 1 (4.4) 2 (8.7) 22 (95.6) 21 (91.3) (100) (0) (14.3) 5 (21.7) 5 (21.7) 11 (47.9) 12 (52.2) (42.9) 3 (13.0) 2 (8.7) (14.3) 3 (13.0) 4 (17.4) (42.9) 20 (87.0) 19 (82.6) (57.1) 20 (87.0) 19 (82.6) 3 (13.0) 4 (17.4) (28.6) (71.4) 4 (17.4) 4 (17.4) (28.6) (14.2) 12 (52.2) 14 (60.9) (85.7) 11 (47.8) 9 (39.1) (14.3) 0 (0) 2 (8.7) 23 (100) 21 (91.3) (71.4) (28.6) 11 (47.8) 8 (34.8) (0) 0 (0) 0 (0) (100) 0 (0) 1 (4.4) (0) 8 (34.8) 9 (39.1) (28.6) 15 (65.2) 14 (60.9) (71.4) 4 (17.4) 2 (8.7) 19 (82.6) 21 (91.3) (57.1) (42.9) (85.7) 5 (21.7) 1 (4.4) (0) 12 (52.2) 14 (60.9) (0) 18 (78.3) 14 (60.9) (85.7) 5 (21.7) 9 (39.1) (14.3) 8 (34.8) 9 (39.1) 15 (65.2) 14 (60.9) (57.1) (42.9) (14.3) 13 (56.5) 16 (69.6) (85.7) 8 (34.8) 5 (21.7) (14.3) 2 (8.7) 2 (8.7) (0) 15 (65.2) 11 (47.8) (71.4) 3 (13.1) 8 (34.8) (28.6) 0 (0) 3 (13.0) (0) 23 (100) 21 (91.3) (85.7) 0 (0) 2 (8.7) (14.3) 5 (21.7) 4 (17.4) (14.3) 2 (8.7) 4 (17.4) (0) 6 (26.1) 3 (13.0) 10 (43.5) 12 (52.2) (71.4) (14.3) 5 (21.7) 4 (17.4) 1 (4.4) 1 (4.4) 0 (0) 22 (95.6) 22 (95.6) 7 (100) (14.3) 2 (8.7) 4 (17.4) (0) 6 (26.1) 3 (13.0) (14.3) 10 (43.5) 12 (52.2) (71.4) 2 (8.7) 1 (4.4) 2 (28.6) 21 (91.3) 22 (95.6) 5 (71.4)	0.327 0.019 0.009 0.840 0.462 1.000 1.000 0.688 0.295 0.993 0.340 0.048 1.000 0.138 ≤0.001 0.395 1.000 0.718 0.110 0.345 0.812 1.000 0.191

2 Table II. Relapse rate according to diagnosis

		Relapse	No relapse	P-value
		N = (%)	N = (%)
	Diagnosis	26 (100)	(100)
	AD	2 (7.7)	(5.3)
	ACD	4 (15.4)	(6.8)	0.238
	ICD	20 (76.9)	(57.9)
	Diagnostic precision	8 (100)	(100)
	Dyshidrotic eczema Hyperkeratotic eczema	4 (50.0) 4 (50.0)	(70.0) (30.0)	0.630
	Relapse treatment	26 (100)	(100)
	Only preventive measures	7 (26.9)	(0)
	Local treatment	15 (57.7)	(0)	≤0.001
	Systemic treatment	4 (15.4)	(0)
	Atopy	26 (100)	(100)
	yes no	15 (57.7) 11 (42.3)	(57.9) (42.1)	1.000
	Age	26 (100)	(100)
	<30 years	4 (15.4)	(36.8)
	30-50 years	11 (42.3)	(26.4)	0.259
	>50 years	11 (42.3)	(36.8)
	Professional roles	26 (100)	(100)
	Administrative profession	5 (19.2)	(31.6)
	Health and cleaning profession	6 (23.1)	(10.5)
	Mechanics, farmers, craftsmen and metal	14 (53.9)	(36.8)	0.168
	workers
	Food and catering workers	1 (3.8)	(21.1)

5.1.3 Table III. Tobacco data

	5.1.
		Tobacco	No tobacco	P-value
		N = (%)	N = %
	Treatment effect	13 (100)	(100)
	Healing	5 (38.5)	(44.4)
	Improvement	7 (53.8)	(38.9)	0.688
	No effect	1 (7.7)	(16.7)
	Relapse	12 (100)	(100)
	Yes No	9 (75.0) 3 (25.0)	(57.1) (42.9)	0.429
	Professionnal status after the treatment	13 (100)	(100)
	Same profession	10 (76.9)	(83.3)
	Change profession	1 (7.7)	(5.6)	1.000
	Unemployed due to eczema	2 (15.4)	(11.1)

4 Table IV. Stress data

		Stress		No stress	P-value
		N = (%)	N = %
	Treatment effect		16 (100)	(100)
	Healing		9 (56.2)	(47.4)
	Improvement		6 (37.5)	(42.1)	0.889
	No effect		1 (6.3)	(10.5)
	Relapse		15 (100)	(100)
	Yes No		10 (66.7) 5 (33.3)	(56.2) (43.8)	0.716
	Professionnal status after the treatment	16 (100)	(100)
	Same profession		13 (81.2)	(84.2)
	Change profession		1 (6.3)	(5.3)	1.000
	Unemployed due to eczema		2 (12.5)	(10.5)
		Sample size
		N= (%)
	Side effects	53 (100)
	Yes	22 (41.5)
	No	31 (58.5)
	Number of side effects	15 (100)
	1	11 (73.3)
	2	4 (7.5)

5.1.5 Table V. Side effects

Type of side effects 15 (100)

		Patients healed depending on the			Patients improved depending on the
		duration of treatment				duration of treatment
	100%						100%
	80%						80%
	60%						60%
	40%						40%
	20%						20%
	0%	≤6 months	7 to 12	13 to 18	≥24 months	Duration of treatment	0%	≤6 months	7 to 12	13 to 18	≥24 months	Duration of treatment
			months	months					months	months
		Relapse rate depending on the duration
			of treatment
	100%						100%
	80%						80%
	60%						60%
	40%						40%
	20%						20%
	0%	≤6 months	7 to 12	13 to 18	≥24 months	Duration of treatment	0%	≤6 months	7 to 12
			months	months					months
	Headaches		8 (53.3)
	Abnormal lipid levels		4 (26.7)
	Skin			4 (26.7)
	Severe anxiety		1 (6.7)
	Asthenia		2 (13.3)

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comme l'asthme ou le psoriasis.[START_REF] Moberg | Hand eczema and quality of life: a population-based study[END_REF] Les facteurs liés à l'exposition professionnelle ont l'impact le plus important avec la perte ou le changement d'emploi.[START_REF] Cazzaniga | Chronic hand eczema: A prospective analysis of the Swiss CARPE registry focusing on factors associated with clinical and quality of life improvement[END_REF] Ainsi, même si un changement de profession a un effet bénéfique sur les paramètres de l'eczéma, il a aussi un effet négatif sur la qualité de vie.[START_REF] Caroe | Job change facilitates healing in a cohort of patients with occupational hand eczema[END_REF] De plus, les coûts indirects liés à la pathologie sont particulièrement élevés. L'alitrétinoïne pourrait réduire ces coûts en évitant la perte d'emploi chez ces patients.Par conséquent, le but de cette étude est d'étudier l'impact du traitement par Alitrétinoïne (TOCTINO®) sur le maintien dans l'emploi des travailleurs présentant un eczéma chronique des mains.

Remerciements

Competing Interests: All authors have declared that no competing interests exist.

Running title: Job retention and alitretinoin

Funding: none.

Conclusion:

Alitretinoin has a positive impact on job retention in patients with CHE refractory to topical corticosteroids. However, preventive measures should shouldbe systematically combined to limit the number of relapses after stopping treatment. Keywords: Toctino; Alitretinoin; chronic hand eczema; job retention; occupational hand eczema; prevention.

Questionnaire

DONNÉES GÉNÉRALES

INFORMATIONS CONCERNANT VOTRE ECZEMA DES MAINS

Cécile FRUGIER

Maintien dans l'emploi des travailleurs présentant un eczéma chronique des mains et traités par Alitrétinoïne.

Thèse