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while 2&#37; to 4&#37; have disease that does not respond to treatment with topical corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In Spain&#44; an estimated 5000 people have severe&#44; refractory hand eczema&#44; and most of these are working-age adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">6&#44;7</span></a> CHE can cause work-related difficulties and may also be associated with social stigma&#44; leading to possible rejection and impaired patient quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Severe CHE is treated with potent topical corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> Other treatment possibilities are topical calcineurin inhibitors&#44; phototherapy with psoralens and long-wave UV radiation &#40;PUVA&#41;&#44; and systemic treatments with corticosteroids or immunosuppressants&#44; such as ciclosporin&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">10&#8211;12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Alitretinoin is the only oral treatment currently approved by the Spanish Agency of Medicines and Medical Devices &#40;AEMPS&#41; for use in severe CHE that is unresponsive to treatment with potent topical corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a> Alitretinoin is an intracellular retinoid receptor pan-agonist&#46; It regulates cell multiplication&#44; differentiation&#44; and apoptosis&#44; and also has immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a> Its efficacy and safety in the treatment of severe CHE have been evaluated in adult patients administered daily doses of 10 to 30<span class="elsevierStyleHsp" style=""></span>mg over 12 to 24 weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">4&#44;15&#8211;17</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The main aim of this study was to describe the use of alitretinoin to treat CHE within the Spanish public health system&#46; We provide a detailed description of the sociodemographic and clinical characteristics of the patients treated&#44; their response and adherence to treatment&#44; their health-related quality of life&#44; and the overall level of satisfaction with the drug among prescribing physicians&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Design</span><p id="par0030" class="elsevierStylePara elsevierViewall">We conducted a descriptive&#44; observational&#44; exploratory&#44; cross-sectional study consisting of a chart review of patients with CHE treated with alitretinoin within the Spanish public health system between July and September 2012&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study Population</span><p id="par0035" class="elsevierStylePara elsevierViewall">At the time of the study&#44; alitretinoin was only available through hospitals&#44; specialized dermatology units&#44; and hospital pharmacies following authorization from the AEMPS&#46; All patients treated with alitretinoin during the study period were identified from medical records&#46; We included patients aged over 18 years with a diagnosis of CHE who had been treated with alitretinoin and whose medical records contained information pertaining to at least 1 follow-up visit at the time of data collection&#46; We excluded patients with a diagnosis other than CHE involving skin infections or other skin disorders&#44; of any etiology&#44; that could interfere with the evaluation of response to alitretinoin&#46; The patients were selected and included in the study sequentially&#44; not randomly&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Twenty-one public hospitals were invited to participate in the study&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study Variables</span><p id="par0045" class="elsevierStylePara elsevierViewall">Using a purpose-designed case report form&#44; we recorded various sociodemographic variables &#40;age&#44; sex&#44; job status and sector&#44; and contact with substances associated with CHE&#41; and the following clinical variables&#58; associated concomitant diseases &#40;e&#46;g&#46;&#44; atopic dermatitis&#44; allergy&#44; asthma&#44; and rhinoconjunctivitis&#41;&#59; personal history of disease &#40;diabetes&#44; thyroid disease&#44; liver failure&#44; kidney failure&#44; hypercholesterolemia&#44; hypertriglyceridemia&#44; hypervitaminosis A&#44; hypertension&#44; obesity&#44; and other dermatologic or systemic diseases&#41;&#59; date of diagnosis and diagnostic tests performed&#59; type&#44; location&#44; and severity of CHE&#59; associated signs and symptoms&#59; dose&#44; frequency&#44; and duration of alitretinoin treatment&#59; previous treatments for CHE&#59; concomitant treatments unrelated to CHE and concomitant treatments for CHE&#59; occurrence and severity of adverse events&#59; treatment response assessments by the treating physician &#40;including Physician Global Assessment&#44; Patient Global Assessment&#44; and modified Total Lesion Symptom Score<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a>&#41;&#59; treatment response&#59; laboratory tests ordered during diagnosis and follow-up&#59; results of these tests&#59; and pregnancy prevention plan where relevant&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">To evaluate physician satisfaction with response to treatment&#44; coinciding with the data collection phase of the study&#44; the participating physicians were asked to complete a purpose-designed questionnaire &#40;available as supplementary material&#41; regarding their satisfaction with the use of alitretinoin in the study population&#44; the type of clinical response obtained&#44; and the level of treatment adherence and compliance&#46; The questionnaire also contained items related to satisfaction with prescribing conditions and adherence to recommendations for the use of alitretinoin&#46; The questions were answered using a 5-point Likert-type scale &#40;1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>not at all satisfied&#44; 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>not very satisfied&#44; 3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>satisfied&#44; 4<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>quite satisfied&#44; and 5<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>very satisfied&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical Requirements</span><p id="par0055" class="elsevierStylePara elsevierViewall">The retrospective design of the study required the participating hospitals to have a policy in place that met the conditions of confidentiality and nontraceability under the Spanish Data Protection Law&#46; The study protocol was approved by the clinical research ethics committee at Hospital Puerta de Hierro&#44; in Madrid&#44; Spain&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Participating Hospitals and Number of Medical Records Reviewed</span><p id="par0060" class="elsevierStylePara elsevierViewall">Of the 21 hospitals approached&#44; 13 agreed to participate in the study&#59; they were located in 5 of Spain&#39;s autonomous communities&#58; Andalusia &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; Aragon &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44; Castilla-la-Mancha &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; Catalonia &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; and Madrid &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#46; Seventy-two relevant medical records were identified&#44; and 62 &#40;86&#37;&#41; of these met the inclusion criteria&#46; The reasons for exclusion were a change in diagnosis from CHE to psoriasis during treatment &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44; treatment for psoriasis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44; diagnosis of chronic eczema with foot involvement only &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; no clinical history &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44; and no clinical follow-up &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Sociodemographic Characteristics</span><p id="par0065" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the patients&#8217; sociodemographic characteristics and employment situation&#46; The mean &#40;SD&#41; age of the patients was 53 &#40;13&#41; years&#44; and there was a similar proportion of men &#40;46&#46;8&#37;&#41; and women &#40;53&#46;2&#37;&#41;&#46; Approximately 40&#46;3&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41; were in employment at the time of the study&#59; 9&#46;7&#37; were homemakers&#44; 9&#46;7&#37; were pensioners&#44; and 1&#46;6&#37; were unemployed&#46; Most patients were working in the textile&#44; chemical&#44; or plastics industries &#40;11&#46;3&#37;&#41;&#44; followed by the domestic work sector &#40;9&#46;7&#37;&#41;&#44; the construction sector &#40;8&#46;1&#37;&#41;&#44; and the hotel and catering industry &#40;8&#46;1&#37;&#41;&#46; Two patients mentioned that CHE had been a determining factor for changing employment&#44; and 6 mentioned it as a reason for temporarily not being able to work&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Diagnosis of CHE</span><p id="par0070" class="elsevierStylePara elsevierViewall">Tests were used to diagnose CHE in 75&#46;8&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>47&#41;&#46; The mean &#40;SD&#41; number of tests was 1&#46;7 &#40;0&#46;6&#41; and the most common tests were patch tests &#40;66&#46;1&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; and biopsy &#40;29&#46;0&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The most common subtype of CHE was hyperkeratotic fissured hand eczema &#40;29&#46;0&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#41;&#46; Eight patients &#40;12&#46;9&#37;&#41; had more than 1 subtype&#46; CHE was observed most frequently on the palms and backs of the hands &#40;69&#46;35&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>43 and 16&#46;13&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#44; respectively&#41;&#46; Just over two-thirds of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#41; had hand involvement only&#44; but 19&#46;35&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#41; and 11&#46;29&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; had involvement of 2 and 3 sites&#44; respectively&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> shows the additional sites affected&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">At least 1 symptom was recorded for 62&#46;9&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39&#41;&#46; Symptoms included pruritus &#40;61&#46;3&#37;&#41;&#44; pain &#40;16&#46;1&#37;&#41;&#44; and burning &#40;3&#46;2&#37;&#41;&#46; Pruritus was mild in 2 cases&#44; moderate in 3&#44; and intense in 17&#46; Severity of involvement was not specified in the remaining 16 cases&#46; Pain&#44; in turn&#44; was moderate in 2 cases &#40;16&#46;1&#37;&#41;&#44; intense in 4&#44; and not specified in another 4&#46; Finally&#44; burning was described as moderate in 2 patients &#40;3&#46;2&#37;&#41;&#46; In total&#44; 90&#46;3&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>56&#41; had clinical manifestations of CHE&#44; namely reddening&#44; flaking&#44; vesicles&#44; edema&#44; and cracks&#46; The most common signs were flaking &#40;62&#46;9&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39&#41;&#44; reddening &#40;45&#46;2&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#41;&#44; and cracks &#40;38&#46;7&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Severity of CHE at the time of diagnosis was noted for 69&#46;3&#37; of patients&#46; The intensity of the eczema was recorded using different terms &#40;e&#46;g&#46;&#44; <span class="elsevierStyleItalic">severe</span>&#44; <span class="elsevierStyleItalic">intense</span>&#44; <span class="elsevierStyleItalic">considerable</span>&#41;&#44; which were considered equivalent for our analysis&#46; Nine patients were reported to have severe CHE&#44; while 21 were considered to have moderate CHE &#40;identified by the terms <span class="elsevierStyleItalic">outbreak</span>&#44; <span class="elsevierStyleItalic">moderate</span>&#44; and <span class="elsevierStyleItalic">moderate to intense</span>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There was mention of nonresponse to potent topical corticosteroids in 87&#46;1&#37; of the medical records &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;&#46; This lack of response was identified by terms such as <span class="elsevierStyleItalic">no response</span> &#40;69&#46;4&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>43&#41; and <span class="elsevierStyleItalic">corticosteroid-dependent</span> &#40;9&#46;7&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;&#46; Impact on quality of life was mentioned&#44; together with treatment resistance&#44; in 5 cases &#40;8&#46;1&#37;&#41;&#46; There was no mention of the use of recommended tools to evaluate these characteristics of CHE&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Over half of the patients&#8217; records &#40;58&#46;1&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41; mentioned 1 or more concomitant diseases associated with CHE&#46; The most common ones were atopic dermatitis &#40;22&#46;6&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41;&#44; allergy &#40;16&#46;1&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#44; and rhinitis &#40;9&#46;7&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Prior Treatment to Alitretinoin</span><p id="par0100" class="elsevierStylePara elsevierViewall">The patients in our series received a mean &#40;SD&#41; of 3 &#40;1&#46;6&#41; medications before being prescribed alitretinoin&#46; Topical treatments included corticosteroids &#40;83&#46;9&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#41;&#44; immunomodulators &#40;33&#46;9&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41;&#44; and topical retinoids &#40;25&#46;8&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;&#46; Phototherapy was used in 16&#46;1&#37; of cases &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Over half of the patients &#40;56&#46;4&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>35&#41; received systemic treatment for CHE at some point of their disease&#46; Systemic therapies included oral corticosteroids &#40;43&#46;5&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&#44; immunosuppressants &#40;33&#46;9&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41;&#44; analgesics&#44; and antibiotics &#40;1&#46;6&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;&#46; Antihistamines had been prescribed to 14 patients &#40;22&#46;6&#37;&#41; and antigout agents &#40;e&#46;g&#46;&#44; colchicine&#41; and antimalarials had each been prescribed to 3 patients &#40;4&#46;8&#37;&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Treatment With Alitretinoin</span><p id="par0110" class="elsevierStylePara elsevierViewall">Of the 62 patients included in the study&#44; 83&#46;9&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#41; received a single cycle of alitretinoin&#44; 14&#46;5&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; received 2 cycles&#44; and just 1&#46;6&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41; received 3 cycles&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The mean &#40;SD&#41; time between treatment cycles was 6&#46;7 &#40;8&#46;9&#41; months for the first and second cycle and 16 months for the second and third cycle&#46; Alitretinoin 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d was used in 83&#46;8&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#41; during the first cycle and in 66&#46;7&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; during the second one&#46; The patient who received a third cycle was also prescribed alitretinoin 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d for this last cycle&#46; The initial dose of 30<span class="elsevierStyleHsp" style=""></span>mg was reduced to 10<span class="elsevierStyleHsp" style=""></span>mg in 1 patient &#40;1&#46;6&#37;&#41; due to headache&#44; and in another patient&#44; an initial dose of 10<span class="elsevierStyleHsp" style=""></span>mg was increased to 30<span class="elsevierStyleHsp" style=""></span>mg on day 20&#46; During the second cycle&#44; the approved dose was changed to a 30-mg dose every 48<span class="elsevierStyleHsp" style=""></span>hours in 2 patients &#40;22&#46;2&#37;&#41;&#46; The median duration of treatment was 15&#46;9 weeks &#40;range&#44; 2-82 weeks&#41; for the first cycle and 8&#46;3 weeks &#40;range&#44; 4-65 weeks&#41; for the second cycle&#46; Duration of treatment in the only third cycle administered was 65 days&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The median time from onset of alitretinoin treatment to the first evaluation of response was 35 days &#40;range&#44; 0-607 days&#41; for the first cycle and 42 days &#40;range&#44; 0-61 days&#41; for the second cycle&#46; Time to evaluation was 90 days for the patient who received the third treatment cycle&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Use of a recommended tool for assessing treatment response was recorded in 35&#46;5&#37; of cases&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the results per cycle&#46; In most cases&#44; response to treatment &#40;clear or almost clear hands&#41; was based on the physician&#39;s clinical assessment&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Considering the data recorded for treatment response&#44; an improvement in CHE was reported for 49 patients &#40;79&#37;&#41; &#40;10 of whom achieved clear or almost clear hands&#41;&#44; while no response was reported for 9 &#40;14&#46;5&#37;&#41;&#46; There was no mention of response in 4 cases &#40;6&#46;4&#37;&#41;&#46; Improvement was observed in 4 &#40;44&#46;4&#37;&#41; of the 9 patients who received a second cycle of treatment&#46; For this cycle&#44; there was 1 nonresponder &#40;11&#46;1&#37;&#41; and no mention of response in 4 cases &#40;44&#46;4&#37;&#41;&#46; Clinical improvement was observed at the first follow-up visit for the patient who underwent the third cycle of alitretinoin&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Approximately 43&#46;5&#37; of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41; were prescribed a concomitant topical treatment&#44; namely emollients &#40;22&#46;6&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41;&#44; high-potent corticosteroids &#40;19&#46;4&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#41;&#44; and potent corticosteroids &#40;3&#46;2&#37;&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46; Four patients &#40;6&#46;5&#37;&#41; were coadministered systemic corticosteroids&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Safety Monitoring</span><p id="par0140" class="elsevierStylePara elsevierViewall">Almost all of the patients&#8217; medical records &#40;98&#46;4&#37;&#41; included information on laboratory tests used to monitor the safety of alitretinoin treatment&#46; A median of 2 tests &#40;range&#44; 0-13 tests&#41; was performed per patient&#46; Most patients &#40;93&#46;4&#37;&#41; showed biochemical alterations during the different treatment cycles&#46; The most common alterations were lipid profile alterations &#40;hypercholesterolemia&#44; 32&#46;3&#37;&#59; hypertriglyceridemia&#44; 3&#46;2&#37;&#59; and hypercholesterolemia and hypertriglyceridemia&#44; 6&#46;5&#37;&#41;&#44; followed by changes in white blood cell count &#40;3&#46;2&#37;&#41;&#44; elevated thyroid stimulating hormone levels &#40;3&#46;2&#37;&#41;&#44; and hyperglycemia &#40;1&#46;6&#37;&#41;&#46; None of these alterations led to an interruption of treatment&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Pregnancy Prevention Plans</span><p id="par0145" class="elsevierStylePara elsevierViewall">Of the 33 women studied&#44; 20 &#40;60&#46;6&#37;&#41; were of reproductive age and therefore should have been following a pregnancy prevention plan during alitretinoin treatment&#46; There was&#44; however&#44; no mention of contraceptive methods in the records of 70&#46;0&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#41; of these patients&#46; Of the remaining 6 women&#44; 4 had been advised to take oral contraceptives&#46; The other 2 did not require a pregnancy prevention plan&#44; as 1 had had a hysterectomy and the other was with a partner who had undergone a vasectomy&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Safety</span><p id="par0150" class="elsevierStylePara elsevierViewall">There was no mention of adverse events in 18 &#40;29&#37;&#41; of the 62 patients studied&#46; Seventeen patients &#40;27&#46;4&#37;&#41; did not experience any adverse effects&#44; and 27 &#40;43&#46;5&#37;&#41; experienced at least 1 adverse effect associated with alitretinoin&#46; The most common effect was headache &#40;25&#46;8&#37;&#41;&#44; followed by xerophthalmia and xerosis &#40;4&#46;8&#37; in both cases&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Alitretinoin treatment was interrupted in 19 patients&#46; The reasons for interruption were a loss of response &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&#44; worsening of CHE &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#44; and adverse effects &#40;headache and swelling at night&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Physician Satisfaction With Alitretinoin Treatment</span><p id="par0160" class="elsevierStylePara elsevierViewall">All the dermatologists surveyed were satisfied with treatment effectiveness and duration&#44; type of response and duration&#44; and safety and tolerability&#46; They all mentioned that they would recommend alitretinoin for the treatment of CHE&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Almost all of the dermatologists &#40;91&#46;7&#37;&#41; were satisfied&#44; quite satisfied&#44; or very satisfied with the percentage of responders observed in their practice&#46; The same proportion also noted that treatment adherence or compliance &#40;defined as &#8220;the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen&#8221;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a>&#41; was better with alitretinoin than with other treatments prescribed for CHE&#46; In addition&#44; 83&#46;3&#37; observed better adherence to alitretinoin treatment than with the most common treatments used in CHE&#46; Seventy-five percent of dermatologists considered that patients treated with alitretinoin had been able to return to work sooner than if they had received other treatments&#46; Two-thirds of the dermatologists surveyed stated that they were not satisfied with the dispensing and prescribing conditions in place at the time of the study &#40;compassionate use&#41;&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0170" class="elsevierStylePara elsevierViewall">The World Health Organization &#40;WHO&#41; encourages studies that investigate the use of medication in routine clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> According to the WHO&#44; over 50&#37; of drugs are prescribed&#44; dispensed&#44; or sold inadequately&#44; and in addition&#44; over 50&#37; of patients fail to take drugs correctly&#46; Inappropriate use of medicines has direct repercussions in terms of undesirable adverse effects&#44; poor results&#44; and inappropriate use of health care resources&#46; In this study&#44; we have described how alitretinoin is routinely used in clinical practice by dermatologists with experience in both the treatment of CHE and the use of oral retinoids&#46; Our findings show that alitretinoin is not entirely used in accordance with the recommendations in the summary of product characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a> However&#44; the compilation of data was complicated by the fact that the participating hospitals used different documentation criteria for their medical records&#46; Compliance with recommendations in the medical literature on how to document treatment response was also suboptimal considering that response is a key factor in the decision regarding whether or not to continue treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Despite the limitations inherent to the design of our study&#44; our results show good response to treatment with alitretinoin and acceptable tolerability&#46; Our findings for treatment effectiveness and safety&#44; patient characteristics&#44; and clinical manifestations of CHE coincide those reported by a prospective&#44; descriptive&#44; observational study performed in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> That study reported very similar complete and partial response rates to ours &#40;clear and almost clear hands&#41; and also described a very similar adverse event profile&#44; with a predominance of headache&#46; Our study differs in only 1 aspect&#44; which was that the most common subtype of CHE in our series was hyperkeratotic fissured hand eczema &#40;29&#46;03&#37;&#41;&#46; Our findings&#44; however&#44; are limited by the heterogeneous definitions and recording of criteria related to disease severity&#44; chronicity&#44; concomitant treatments&#44; and resistance to previous treatments&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">It should be noted that both the use of alitretinoin and the clinical information available at the time of the study were marked by a degree of uncertainty&#46; Such uncertainty is typical in the context of recurrent and disabling disorders&#44; such as <span class="elsevierStyleGrantSponsor" id="gs1">CHE</span>&#44; for which alternative treatments are limited&#44; frequently used off-label&#44; and associated with undetermined clinical response&#46; Alitretinoin&#44; however&#44; differs in this respect&#44; as its use in severe&#44; refractory <span class="elsevierStyleGrantSponsor" id="gs2">CHE</span> is approved and supported by clinical response data&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">15&#8211;17</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Because severe&#44; refractory CHE is relatively uncommon in Spain and access to alitretinoin is restricted&#44; there were relatively few candidates for inclusion in this study&#46; Nonetheless&#44; our findings are important as they describe how a specific drug is routinely used to treat a disease in the Spanish public health care system&#44; although our results cannot be extrapolated to other health care areas&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The data compiled show trends in usage and the need to standardize the documentation of patient information and the use of tools for evaluating clinical response and treatment goals&#46; Our findings for the levels of satisfaction among dermatologists using alitretinoin should also be interpreted within the context of the number of physicians who answered the questionnaire&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">In conclusion&#44; alitretinoin is used to treat severe&#44; refractory CHE&#44; is mainly used at a dose of 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d administered in a single cycle&#44; and achieves satisfactory clinical response in the opinion of the treating physicians&#46; The adverse events observed were all predictable and consistent with those seen in systemic retinoid therapy&#46; Finally&#44; the dermatologists surveyed all agreed that the clinical benefits associated with alitretinoin favored treatment adherence and a speedier return to work&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Ethical Disclosures</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Protection of humans and animals</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that no tests were carried out in humans or animals for the purpose of this study&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Confidentiality of data</span><p id="par0205" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data appear in this article&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Right to privacy and informed consent</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data appear in this article&#46;</p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Funding</span><p id="par0215" class="elsevierStylePara elsevierViewall">This study was sponsored by Almirall&#44; SA&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflicts of Interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">Dr S Urrutia and Dr G&#160;Roustan report having received fees for contributing their expert knowledge to the topic of interest&#46; S&#160;Paz and L&#160;Liz&#225;n work for an independent research entity and have received fees for contributing to the development and coordination of the original research project and for preparing an initial draft of this manuscript&#46; All fees were paid by the study sponsor&#44; Amirall SA&#46; Dr MJ Plazas and Dr S&#160;Armengol work at Amirall SA&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Nonetheless&#44; the authors declare that the results of the research described in this article&#44; together with the analysis and interpretation of the result&#44; are based on the free opinion and consensus of the authors&#44; and that no conflicts arose in relation to the production or dissemination of these results&#46;</p></span></span>"
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              "titulo" => "Design"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Study Population"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Study Variables"
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              "titulo" => "Ethical Requirements"
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              "titulo" => "Participating Hospitals and Number of Medical Records Reviewed"
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    "fechaRecibido" => "2015-06-24"
    "fechaAceptado" => "2015-08-01"
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            1 => "Eczema"
            2 => "Chronic hand eczema"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hand eczema affects nearly 10&#37; of the population&#46; The condition becomes severe and chronic in 5&#37; to 7&#37; of cases and is refractory to topical corticosteroids in 2&#37; to 4&#37;&#46; This study aimed to describe the current use of oral alitretinoin in treating Spanish national health system patients with hand eczema that is refractory to potent topical corticosteroids&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Observational&#44; descriptive&#44; exploratory&#44; cross-sectional study based on the retrospective analysis of records for patients with hand eczema treated with alitretinoin in the Spanish national health system&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We reviewed the records for 62 patients in 13 hospitals in 5 different administrative areas &#40;autonomous communities&#41; of Spain&#46; Alitretinoin was usually used at a dosage of 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#46; In most cases the physician judged the clinical response to be satisfactory after a single cycle&#46; The recorded adverse effects were foreseeable and of the type reported for systemic retinoids&#46; The dermatologists agreed that the clinical benefits achieved with alitretinoin favored adherence to treatment and an early return to work&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The results show that oral alitretinoin is being used according to established recommendations and that response is good&#44; with few adverse effects&#46; The dermatologists agreed that the benefits favored adherence and improved the patients&#8217; health related quality of life&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El eczema de manos &#40;ECM&#41; afecta a cerca del 10&#37; de la poblaci&#243;n&#44; present&#225;ndose entre el 5 y el 7&#37; de los casos como una enfermedad cr&#243;nica grave y siendo refractario al tratamiento con corticoides t&#243;picos entre el 2 y el 4&#37; de las veces&#46; El prop&#243;sito del art&#237;culo es describir el uso de la alitretino&#237;na oral en pacientes con ECM refractario a corticoides t&#243;picos potentes en el &#225;mbito sanitario p&#250;blico espa&#241;ol&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional descriptivo&#44; exploratorio&#44; transversal&#44; basado en la revisi&#243;n retrospectiva de historias cl&#237;nicas de pacientes con ECM en tratamiento con alitretino&#237;na en el &#225;mbito sanitario p&#250;blico espa&#241;ol&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se revisaron 62 historias cl&#237;nicas de pacientes de 13 centros distribuidos en 5 comunidades aut&#243;nomas del territorio espa&#241;ol&#46; Alitretino&#237;na se utiliz&#243; predominantemente a dosis de 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#237;a&#44; principalmente en un &#250;nico ciclo&#44; tras el cual la mayor&#237;a de pacientes lograron una respuesta cl&#237;nica satisfactoria seg&#250;n el juicio m&#233;dico&#46; Los eventos adversos fueron todos previsibles y en l&#237;nea con los tratamientos sist&#233;micos con retinoides&#46; Los dermat&#243;logos estuvieron de acuerdo en que los beneficios cl&#237;nicos logrados con alitretino&#237;na favorec&#237;an la adherencia al tratamiento y una reincorporaci&#243;n m&#225;s r&#225;pida de los pacientes al trabajo&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados muestran un uso de alitretino&#237;na oral en l&#237;nea con las recomendaciones establecidas as&#237; como la buena respuesta al tratamiento asociado y los pocos efectos adversos&#46; Los dermat&#243;logos coinciden que los beneficios alcanzados favorecen la adherencia al tratamiento y mejoran la calidad de vida relacionada con la salud de los pacientes&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Urrutia S&#44; Roustan G&#44; Plazas MJ&#44; Armengol S&#44; Paz S&#44; Lizan L&#46; Uso de la alitretino&#237;na oral para el tratamiento del eczema cr&#243;nico de manos grave y refractario al tratamiento en el sistema sanitario p&#250;blico espa&#241;ol&#58; descripci&#243;n y an&#225;lisis de la pr&#225;ctica cl&#237;nica actual&#46; Actas Dermosifiliogr&#46; 2016&#59;107&#58;142&#8211;148&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribution of Sample According to Sites of Chronic Hand Eczema Other Than the Hands&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mean &#40;SD&#41; age&#44; y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;73 &#40;12&#46;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male sex&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Currently in employment&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Change of work sector following diagnosis of CHE&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inability to work due to CHE&#44; &#37;&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "Guideline on the management of hand eczema ICD-10 Code&#58; L20&#46; L23&#46; L24&#46; L25&#46; L30"
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Journal Information
Vol. 107. Issue 2.
Pages 142-148 (March 2016)
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5279
Vol. 107. Issue 2.
Pages 142-148 (March 2016)
Original Article
Full text access
Oral Alitretinoin in the Treatment of Severe Refractory Chronic Hand Eczema in the Spanish National Health System: Description and Analysis of Current Clinical Practice
Uso de la alitretinoína oral para el tratamiento del eczema crónico de manos grave y refractario al tratamiento en el sistema sanitario público español: descripción y análisis de la práctica clínica actual
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S. Urrutiaa, G. Roustanb, M.J. Plazasc, S. Armengolc, S. Pazd,
Corresponding author
spaz@outcomes10.com

Corresponding author.
, L. Lizand
a Servicio de Dermatología, Hospital Universitario Ramón y Cajal, Madrid, Spain
b Servicio de Dermatología, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
c Departamento Médico, Almirall SA, Barcelona, Spain
d Outcomes’10, Castellón, Spain
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Figures (1)
Tables (2)
Table 1. Sociodemographic Characteristics of Patients With Chronic Hand Eczema (CHE) Treated With Alitretinoin.
Table 2. Distribution of Sample According to Evaluation of Response to Oral Alitretinoin After Each Cycle.
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Additional material (1)
Abstract
Background and objective

Hand eczema affects nearly 10% of the population. The condition becomes severe and chronic in 5% to 7% of cases and is refractory to topical corticosteroids in 2% to 4%. This study aimed to describe the current use of oral alitretinoin in treating Spanish national health system patients with hand eczema that is refractory to potent topical corticosteroids.

Materials and methods

Observational, descriptive, exploratory, cross-sectional study based on the retrospective analysis of records for patients with hand eczema treated with alitretinoin in the Spanish national health system.

Results

We reviewed the records for 62 patients in 13 hospitals in 5 different administrative areas (autonomous communities) of Spain. Alitretinoin was usually used at a dosage of 30mg/d. In most cases the physician judged the clinical response to be satisfactory after a single cycle. The recorded adverse effects were foreseeable and of the type reported for systemic retinoids. The dermatologists agreed that the clinical benefits achieved with alitretinoin favored adherence to treatment and an early return to work.

Conclusions

The results show that oral alitretinoin is being used according to established recommendations and that response is good, with few adverse effects. The dermatologists agreed that the benefits favored adherence and improved the patients’ health related quality of life.

Keywords:
Alitretinoin
Eczema
Chronic hand eczema
Physicians’ practice patterns
Resumen
Introducción

El eczema de manos (ECM) afecta a cerca del 10% de la población, presentándose entre el 5 y el 7% de los casos como una enfermedad crónica grave y siendo refractario al tratamiento con corticoides tópicos entre el 2 y el 4% de las veces. El propósito del artículo es describir el uso de la alitretinoína oral en pacientes con ECM refractario a corticoides tópicos potentes en el ámbito sanitario público español.

Material y métodos

Estudio observacional descriptivo, exploratorio, transversal, basado en la revisión retrospectiva de historias clínicas de pacientes con ECM en tratamiento con alitretinoína en el ámbito sanitario público español.

Resultados

Se revisaron 62 historias clínicas de pacientes de 13 centros distribuidos en 5 comunidades autónomas del territorio español. Alitretinoína se utilizó predominantemente a dosis de 30mg/día, principalmente en un único ciclo, tras el cual la mayoría de pacientes lograron una respuesta clínica satisfactoria según el juicio médico. Los eventos adversos fueron todos previsibles y en línea con los tratamientos sistémicos con retinoides. Los dermatólogos estuvieron de acuerdo en que los beneficios clínicos logrados con alitretinoína favorecían la adherencia al tratamiento y una reincorporación más rápida de los pacientes al trabajo.

Conclusión

Los resultados muestran un uso de alitretinoína oral en línea con las recomendaciones establecidas así como la buena respuesta al tratamiento asociado y los pocos efectos adversos. Los dermatólogos coinciden que los beneficios alcanzados favorecen la adherencia al tratamiento y mejoran la calidad de vida relacionada con la salud de los pacientes.

Palabras clave:
Alitretinoína
Eczema
Eczema crónico de manos
Patrones de práctica del médico
Full Text
Introduction

Chronic hand eczema (CHE) is hand eczema that lasts for over 3 months or that occurs 2 or 3 times in a period of 12 months, despite treatment.1 It is characterized by erythema, vesicles, papules, cracks, hyperkeratosis, pruritus, and pain, and symptoms can range from mild to disabling.2,3 Hand eczema affects approximately 10% of the population4,5; between 5% and 7% of these have severe chronic disease, while 2% to 4% have disease that does not respond to treatment with topical corticosteroids.1

In Spain, an estimated 5000 people have severe, refractory hand eczema, and most of these are working-age adults.6,7 CHE can cause work-related difficulties and may also be associated with social stigma, leading to possible rejection and impaired patient quality of life.8,9

Severe CHE is treated with potent topical corticosteroids.1 Other treatment possibilities are topical calcineurin inhibitors, phototherapy with psoralens and long-wave UV radiation (PUVA), and systemic treatments with corticosteroids or immunosuppressants, such as ciclosporin.10–12

Alitretinoin is the only oral treatment currently approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) for use in severe CHE that is unresponsive to treatment with potent topical corticosteroids.13 Alitretinoin is an intracellular retinoid receptor pan-agonist. It regulates cell multiplication, differentiation, and apoptosis, and also has immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation.14 Its efficacy and safety in the treatment of severe CHE have been evaluated in adult patients administered daily doses of 10 to 30mg over 12 to 24 weeks.4,15–17

The main aim of this study was to describe the use of alitretinoin to treat CHE within the Spanish public health system. We provide a detailed description of the sociodemographic and clinical characteristics of the patients treated, their response and adherence to treatment, their health-related quality of life, and the overall level of satisfaction with the drug among prescribing physicians.

MethodsDesign

We conducted a descriptive, observational, exploratory, cross-sectional study consisting of a chart review of patients with CHE treated with alitretinoin within the Spanish public health system between July and September 2012.

Study Population

At the time of the study, alitretinoin was only available through hospitals, specialized dermatology units, and hospital pharmacies following authorization from the AEMPS. All patients treated with alitretinoin during the study period were identified from medical records. We included patients aged over 18 years with a diagnosis of CHE who had been treated with alitretinoin and whose medical records contained information pertaining to at least 1 follow-up visit at the time of data collection. We excluded patients with a diagnosis other than CHE involving skin infections or other skin disorders, of any etiology, that could interfere with the evaluation of response to alitretinoin. The patients were selected and included in the study sequentially, not randomly.

Twenty-one public hospitals were invited to participate in the study.

Study Variables

Using a purpose-designed case report form, we recorded various sociodemographic variables (age, sex, job status and sector, and contact with substances associated with CHE) and the following clinical variables: associated concomitant diseases (e.g., atopic dermatitis, allergy, asthma, and rhinoconjunctivitis); personal history of disease (diabetes, thyroid disease, liver failure, kidney failure, hypercholesterolemia, hypertriglyceridemia, hypervitaminosis A, hypertension, obesity, and other dermatologic or systemic diseases); date of diagnosis and diagnostic tests performed; type, location, and severity of CHE; associated signs and symptoms; dose, frequency, and duration of alitretinoin treatment; previous treatments for CHE; concomitant treatments unrelated to CHE and concomitant treatments for CHE; occurrence and severity of adverse events; treatment response assessments by the treating physician (including Physician Global Assessment, Patient Global Assessment, and modified Total Lesion Symptom Score18); treatment response; laboratory tests ordered during diagnosis and follow-up; results of these tests; and pregnancy prevention plan where relevant.

To evaluate physician satisfaction with response to treatment, coinciding with the data collection phase of the study, the participating physicians were asked to complete a purpose-designed questionnaire (available as supplementary material) regarding their satisfaction with the use of alitretinoin in the study population, the type of clinical response obtained, and the level of treatment adherence and compliance. The questionnaire also contained items related to satisfaction with prescribing conditions and adherence to recommendations for the use of alitretinoin. The questions were answered using a 5-point Likert-type scale (1=not at all satisfied, 2=not very satisfied, 3=satisfied, 4=quite satisfied, and 5=very satisfied).

Ethical Requirements

The retrospective design of the study required the participating hospitals to have a policy in place that met the conditions of confidentiality and nontraceability under the Spanish Data Protection Law. The study protocol was approved by the clinical research ethics committee at Hospital Puerta de Hierro, in Madrid, Spain.

ResultsParticipating Hospitals and Number of Medical Records Reviewed

Of the 21 hospitals approached, 13 agreed to participate in the study; they were located in 5 of Spain's autonomous communities: Andalusia (n=2), Aragon (n=1), Castilla-la-Mancha (n=2), Catalonia (n=2), and Madrid (n=7). Seventy-two relevant medical records were identified, and 62 (86%) of these met the inclusion criteria. The reasons for exclusion were a change in diagnosis from CHE to psoriasis during treatment (n=1), treatment for psoriasis (n=1), diagnosis of chronic eczema with foot involvement only (n=2), no clinical history (n=1), and no clinical follow-up (n=5).

Sociodemographic Characteristics

Table 1 summarizes the patients’ sociodemographic characteristics and employment situation. The mean (SD) age of the patients was 53 (13) years, and there was a similar proportion of men (46.8%) and women (53.2%). Approximately 40.3% of patients (n=25) were in employment at the time of the study; 9.7% were homemakers, 9.7% were pensioners, and 1.6% were unemployed. Most patients were working in the textile, chemical, or plastics industries (11.3%), followed by the domestic work sector (9.7%), the construction sector (8.1%), and the hotel and catering industry (8.1%). Two patients mentioned that CHE had been a determining factor for changing employment, and 6 mentioned it as a reason for temporarily not being able to work.

Table 1.

Sociodemographic Characteristics of Patients With Chronic Hand Eczema (CHE) Treated With Alitretinoin.

Characteristics
Mean (SD) age, y  52.73 (12.97) 
Male sex, %  46.8 
Currently in employment, %  40.3 
Change of work sector following diagnosis of CHE, %  3.2 
Inability to work due to CHE, %  9.7 
Contact with substances that cause CHE, %  41.9 
Diagnosis of CHE

Tests were used to diagnose CHE in 75.8% of patients (n=47). The mean (SD) number of tests was 1.7 (0.6) and the most common tests were patch tests (66.1%; n=41) and biopsy (29.0%; n=18).

The most common subtype of CHE was hyperkeratotic fissured hand eczema (29.0%; n=18). Eight patients (12.9%) had more than 1 subtype. CHE was observed most frequently on the palms and backs of the hands (69.35%, n=43 and 16.13%, n=10, respectively). Just over two-thirds of patients (n=42) had hand involvement only, but 19.35% (n=12) and 11.29% (n=7) had involvement of 2 and 3 sites, respectively. Figure 1 shows the additional sites affected.

Figure 1.

Distribution of Sample According to Sites of Chronic Hand Eczema Other Than the Hands.

(0.11MB).

At least 1 symptom was recorded for 62.9% of patients (n=39). Symptoms included pruritus (61.3%), pain (16.1%), and burning (3.2%). Pruritus was mild in 2 cases, moderate in 3, and intense in 17. Severity of involvement was not specified in the remaining 16 cases. Pain, in turn, was moderate in 2 cases (16.1%), intense in 4, and not specified in another 4. Finally, burning was described as moderate in 2 patients (3.2%). In total, 90.3% of patients (n=56) had clinical manifestations of CHE, namely reddening, flaking, vesicles, edema, and cracks. The most common signs were flaking (62.9%, n=39), reddening (45.2%, n=28), and cracks (38.7%, n=24).

Severity of CHE at the time of diagnosis was noted for 69.3% of patients. The intensity of the eczema was recorded using different terms (e.g., severe, intense, considerable), which were considered equivalent for our analysis. Nine patients were reported to have severe CHE, while 21 were considered to have moderate CHE (identified by the terms outbreak, moderate, and moderate to intense).

There was mention of nonresponse to potent topical corticosteroids in 87.1% of the medical records (n=54). This lack of response was identified by terms such as no response (69.4%, n=43) and corticosteroid-dependent (9.7%, n=6). Impact on quality of life was mentioned, together with treatment resistance, in 5 cases (8.1%). There was no mention of the use of recommended tools to evaluate these characteristics of CHE.

Over half of the patients’ records (58.1%; n=36) mentioned 1 or more concomitant diseases associated with CHE. The most common ones were atopic dermatitis (22.6%, n=14), allergy (16.1%, n=10), and rhinitis (9.7%, n=6).

Prior Treatment to Alitretinoin

The patients in our series received a mean (SD) of 3 (1.6) medications before being prescribed alitretinoin. Topical treatments included corticosteroids (83.9%, n=52), immunomodulators (33.9%, n=21), and topical retinoids (25.8%, n=16). Phototherapy was used in 16.1% of cases (n=10).

Over half of the patients (56.4%, n=35) received systemic treatment for CHE at some point of their disease. Systemic therapies included oral corticosteroids (43.5%, n=27), immunosuppressants (33.9%, n=21), analgesics, and antibiotics (1.6%, n=1). Antihistamines had been prescribed to 14 patients (22.6%) and antigout agents (e.g., colchicine) and antimalarials had each been prescribed to 3 patients (4.8%).

Treatment With Alitretinoin

Of the 62 patients included in the study, 83.9% (n=52) received a single cycle of alitretinoin, 14.5% (n=9) received 2 cycles, and just 1.6% (n=1) received 3 cycles.

The mean (SD) time between treatment cycles was 6.7 (8.9) months for the first and second cycle and 16 months for the second and third cycle. Alitretinoin 30mg/d was used in 83.8% of patients (n=52) during the first cycle and in 66.7% of patients (n=6) during the second one. The patient who received a third cycle was also prescribed alitretinoin 30mg/d for this last cycle. The initial dose of 30mg was reduced to 10mg in 1 patient (1.6%) due to headache, and in another patient, an initial dose of 10mg was increased to 30mg on day 20. During the second cycle, the approved dose was changed to a 30-mg dose every 48hours in 2 patients (22.2%). The median duration of treatment was 15.9 weeks (range, 2-82 weeks) for the first cycle and 8.3 weeks (range, 4-65 weeks) for the second cycle. Duration of treatment in the only third cycle administered was 65 days.

The median time from onset of alitretinoin treatment to the first evaluation of response was 35 days (range, 0-607 days) for the first cycle and 42 days (range, 0-61 days) for the second cycle. Time to evaluation was 90 days for the patient who received the third treatment cycle.

Use of a recommended tool for assessing treatment response was recorded in 35.5% of cases. Table 2 summarizes the results per cycle. In most cases, response to treatment (clear or almost clear hands) was based on the physician's clinical assessment.

Table 2.

Distribution of Sample According to Evaluation of Response to Oral Alitretinoin After Each Cycle.

EvaluationCycle 1Cycle 2Cycle 3
No.  No.  No. 
Clear hands  12.9  11.1  –  – 
Almost clear hands  3.2  –  –  –  – 
Clinical improvement  31  50  33.3  100 
Good progress  12.9  –  –  –  – 
Lack of response  14.5  11.1  –  – 
No response specified  6.45  44.4  –  – 
Total  62  100  100  100 

Considering the data recorded for treatment response, an improvement in CHE was reported for 49 patients (79%) (10 of whom achieved clear or almost clear hands), while no response was reported for 9 (14.5%). There was no mention of response in 4 cases (6.4%). Improvement was observed in 4 (44.4%) of the 9 patients who received a second cycle of treatment. For this cycle, there was 1 nonresponder (11.1%) and no mention of response in 4 cases (44.4%). Clinical improvement was observed at the first follow-up visit for the patient who underwent the third cycle of alitretinoin.

Approximately 43.5% of patients (n=27) were prescribed a concomitant topical treatment, namely emollients (22.6%, n=14), high-potent corticosteroids (19.4%, n=12), and potent corticosteroids (3.2%, n=2). Four patients (6.5%) were coadministered systemic corticosteroids.

Safety Monitoring

Almost all of the patients’ medical records (98.4%) included information on laboratory tests used to monitor the safety of alitretinoin treatment. A median of 2 tests (range, 0-13 tests) was performed per patient. Most patients (93.4%) showed biochemical alterations during the different treatment cycles. The most common alterations were lipid profile alterations (hypercholesterolemia, 32.3%; hypertriglyceridemia, 3.2%; and hypercholesterolemia and hypertriglyceridemia, 6.5%), followed by changes in white blood cell count (3.2%), elevated thyroid stimulating hormone levels (3.2%), and hyperglycemia (1.6%). None of these alterations led to an interruption of treatment.

Pregnancy Prevention Plans

Of the 33 women studied, 20 (60.6%) were of reproductive age and therefore should have been following a pregnancy prevention plan during alitretinoin treatment. There was, however, no mention of contraceptive methods in the records of 70.0% (n=14) of these patients. Of the remaining 6 women, 4 had been advised to take oral contraceptives. The other 2 did not require a pregnancy prevention plan, as 1 had had a hysterectomy and the other was with a partner who had undergone a vasectomy.

Safety

There was no mention of adverse events in 18 (29%) of the 62 patients studied. Seventeen patients (27.4%) did not experience any adverse effects, and 27 (43.5%) experienced at least 1 adverse effect associated with alitretinoin. The most common effect was headache (25.8%), followed by xerophthalmia and xerosis (4.8% in both cases).

Alitretinoin treatment was interrupted in 19 patients. The reasons for interruption were a loss of response (n=5), worsening of CHE (n=2), and adverse effects (headache and swelling at night) (n=2).

Physician Satisfaction With Alitretinoin Treatment

All the dermatologists surveyed were satisfied with treatment effectiveness and duration, type of response and duration, and safety and tolerability. They all mentioned that they would recommend alitretinoin for the treatment of CHE.

Almost all of the dermatologists (91.7%) were satisfied, quite satisfied, or very satisfied with the percentage of responders observed in their practice. The same proportion also noted that treatment adherence or compliance (defined as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen”19) was better with alitretinoin than with other treatments prescribed for CHE. In addition, 83.3% observed better adherence to alitretinoin treatment than with the most common treatments used in CHE. Seventy-five percent of dermatologists considered that patients treated with alitretinoin had been able to return to work sooner than if they had received other treatments. Two-thirds of the dermatologists surveyed stated that they were not satisfied with the dispensing and prescribing conditions in place at the time of the study (compassionate use).

Discussion

The World Health Organization (WHO) encourages studies that investigate the use of medication in routine clinical practice.18 According to the WHO, over 50% of drugs are prescribed, dispensed, or sold inadequately, and in addition, over 50% of patients fail to take drugs correctly. Inappropriate use of medicines has direct repercussions in terms of undesirable adverse effects, poor results, and inappropriate use of health care resources. In this study, we have described how alitretinoin is routinely used in clinical practice by dermatologists with experience in both the treatment of CHE and the use of oral retinoids. Our findings show that alitretinoin is not entirely used in accordance with the recommendations in the summary of product characteristics.14 However, the compilation of data was complicated by the fact that the participating hospitals used different documentation criteria for their medical records. Compliance with recommendations in the medical literature on how to document treatment response was also suboptimal considering that response is a key factor in the decision regarding whether or not to continue treatment.9

Despite the limitations inherent to the design of our study, our results show good response to treatment with alitretinoin and acceptable tolerability. Our findings for treatment effectiveness and safety, patient characteristics, and clinical manifestations of CHE coincide those reported by a prospective, descriptive, observational study performed in Spain.4 That study reported very similar complete and partial response rates to ours (clear and almost clear hands) and also described a very similar adverse event profile, with a predominance of headache. Our study differs in only 1 aspect, which was that the most common subtype of CHE in our series was hyperkeratotic fissured hand eczema (29.03%). Our findings, however, are limited by the heterogeneous definitions and recording of criteria related to disease severity, chronicity, concomitant treatments, and resistance to previous treatments.

It should be noted that both the use of alitretinoin and the clinical information available at the time of the study were marked by a degree of uncertainty. Such uncertainty is typical in the context of recurrent and disabling disorders, such as CHE, for which alternative treatments are limited, frequently used off-label, and associated with undetermined clinical response. Alitretinoin, however, differs in this respect, as its use in severe, refractory CHE is approved and supported by clinical response data.15–17

Because severe, refractory CHE is relatively uncommon in Spain and access to alitretinoin is restricted, there were relatively few candidates for inclusion in this study. Nonetheless, our findings are important as they describe how a specific drug is routinely used to treat a disease in the Spanish public health care system, although our results cannot be extrapolated to other health care areas.

The data compiled show trends in usage and the need to standardize the documentation of patient information and the use of tools for evaluating clinical response and treatment goals. Our findings for the levels of satisfaction among dermatologists using alitretinoin should also be interpreted within the context of the number of physicians who answered the questionnaire.

In conclusion, alitretinoin is used to treat severe, refractory CHE, is mainly used at a dose of 30mg/d administered in a single cycle, and achieves satisfactory clinical response in the opinion of the treating physicians. The adverse events observed were all predictable and consistent with those seen in systemic retinoid therapy. Finally, the dermatologists surveyed all agreed that the clinical benefits associated with alitretinoin favored treatment adherence and a speedier return to work.

Ethical DisclosuresProtection of humans and animals

The authors declare that no tests were carried out in humans or animals for the purpose of this study.

Confidentiality of data

The authors declare that no private patient data appear in this article.

Right to privacy and informed consent

The authors declare that no private patient data appear in this article.

Funding

This study was sponsored by Almirall, SA.

Conflicts of Interest

Dr S Urrutia and Dr G Roustan report having received fees for contributing their expert knowledge to the topic of interest. S Paz and L Lizán work for an independent research entity and have received fees for contributing to the development and coordination of the original research project and for preparing an initial draft of this manuscript. All fees were paid by the study sponsor, Amirall SA. Dr MJ Plazas and Dr S Armengol work at Amirall SA.

Nonetheless, the authors declare that the results of the research described in this article, together with the analysis and interpretation of the result, are based on the free opinion and consensus of the authors, and that no conflicts arose in relation to the production or dissemination of these results.

Acknowledgments

The authors would like to thank Stiefel/GSK for checking the accuracy of the product information reported in this article.

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Please cite this article as: Urrutia S, Roustan G, Plazas MJ, Armengol S, Paz S, Lizan L. Uso de la alitretinoína oral para el tratamiento del eczema crónico de manos grave y refractario al tratamiento en el sistema sanitario público español: descripción y análisis de la práctica clínica actual. Actas Dermosifiliogr. 2016;107:142–148.

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