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At the time this study was conducted&#44; for moderate&#8211;severe forms&#44; treatments recommended in guidelines include topical corticosteroids and calcineurin inhibitors&#44; phototherapy&#44; short-term oral corticosteroids&#44; conventional immunosuppressants &#40;cyclosporine&#44; mycophenolate mofetil&#44; azathioprine and methotrexate&#44; the last three unapproved for AD&#41;&#44; and dupilumab monoclonal antibody <a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">1&#44;11&#44;12</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Although several recent studies described disease burden in Spain <a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">13&#44;14</span></a>&#44; there is limited evidence on the use of treatments over time and the economic impact of the disease in routine practice conditions&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">This study described sociodemographic and clinical characteristics&#44; treatment patterns&#44; health resource use &#40;HRU&#41; and costs in adults with AD who initiated treatment with systemic drugs or phototherapy in the real-world setting in Spain&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0030" class="elsevierStylePara elsevierViewall">A non-interventional&#44; retrospective&#44; longitudinal study based on electronic medical records in the Big-Pac database in Spain was conducted to describe sociodemographic&#47;clinical characteristics&#44; treatment patterns&#44; HRU and associated costs&#46; Adult patients with AD newly initiating treatment with a systemic drug &#40;oral immunosuppressant&#44; systemic corticosteroid&#44; or biologic&#41; or phototherapy between 01&#47;01&#47;2012 and 31&#47;12&#47;2016 &#40;i&#46;e&#46;&#44; inclusion period&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; were included&#46; Patients were followed-up for 3 years from the date of first systemic treatment initiation or phototherapy &#40;i&#46;e&#46;&#44; index date&#41;&#44; up to 31&#47;12&#47;2019&#46; A 2-year pre-index period was used to verify that no prior records of systemic drugs or phototherapy were documented&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Data confidentiality &#40;anonymous and dissociated&#41; was respected in compliance with Organic Law 3&#47;2018&#44; of December 5&#44; on Protection of Personal Data and guarantee of rights &#40;<a href="https://www.boe.es/eli/es/lo/2018/12/05/3">https&#58;&#47;&#47;www&#46;boe&#46;es&#47;eli&#47;es&#47;lo&#47;2018&#47;12&#47;05&#47;3</a>&#41;&#46; The study was approved by the Ethics Committee of the Consorci Sanitari de Terrassa &#40;Barcelona&#44; Spain&#41; and conducted in accordance with the ethical principles of the Declaration of Helsinki and applicable laws and regulations in Spain&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data source</span><p id="par0040" class="elsevierStylePara elsevierViewall">Data were obtained from the Big-Pac database &#40;Atrys Health-Real Life Data&#44; Madrid&#44; Spain&#41;&#44; which collects computerized and anonymized patient medical records from primary and secondary care&#44; records of drug dispensation and other complementary databases from seven regions in Spain&#46; The population assigned to the health centers from which data were extracted included 1&#44;867&#44;108 inhabitants at the time of data extraction and may be considered representative of the Spanish population <a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">15</span></a>&#46; The database is registered in The European Network of Centers for Pharmacoepidemiology and Pharmacovigilance &#40;ENCePP&#174;&#41; &#40;<a href="http://www.encepp.eu/encepp/viewResource.htm?id=29236">http&#58;&#47;&#47;www&#46;encepp&#46;eu&#47;encepp&#47;viewResource&#46;htm&#63;id&#61;29236&#35;</a>&#41;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study population</span><p id="par0045" class="elsevierStylePara elsevierViewall">Patients meeting the following inclusion criteria at the index date were included&#58; &#40;a&#41; had a record of AD diagnosis prior to the index date according to the International Classification of Diseases&#44; Ninth Revision&#44; Clinical Modification &#40;ICD-9-CM&#41; codes &#40;691&#46;8 &#8211; other atopic dermatitis and related conditions or 692&#46;9 &#8211; contact dermatitis and other eczema&#44; unspecified cause&#44; with &#8216;allergic&#8217; or &#8216;atopic&#8217; in the &#8216;description&#8217; field of diagnosis in the database&#41;&#59; &#40;b&#41; started treatment with phototherapy or a systemic drug between 01&#47;01&#47;2012 and 31&#47;12&#47;2016&#59; &#40;c&#41; aged at least 18 years&#44; &#40;d&#41; patient included in the prescriptions program to obtain the medical prescriptions &#40;with proven record of the daily dose&#44; the time interval and the duration of each treatment being administered&#59; 2 or more prescriptions during the monitoring period&#41;&#59; &#40;e&#41; with 2 or more healthcare records&#59; &#40;f&#41; continuously registered in the database for at least 3 years from the index date&#46; Patients were excluded if they were &#40;a&#41; transferred to other centers&#44; displaced or out of area&#44; &#40;b&#41; permanently institutionalized&#44; &#40;c&#41; had a terminal disease or &#40;d&#41; had a record of phototherapy or systemic medication in the 2-year pre-index period&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Only patients with an AD-related ICD-9-CM code documented for at least one prescription of systemic treatment during the inclusion period were included in the analysis&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Study endpoints and variables</span><p id="par0055" class="elsevierStylePara elsevierViewall">Sociodemographic and clinical data were obtained at or prior to the index date&#44; including age&#44; gender&#44; BMI&#44; time from AD diagnosis&#44; age at AD onset&#46; Most frequent &#40;frequency &#8805;5&#37;&#41; clinically relevant comorbidities were described based on ICD-9-CM codes &#40;<a class="elsevierStyleCrossRef" href="#sec0085">Supplementary material Table 1</a>&#41;&#46; The mean &#40;SD&#41; number of comorbidities per patient was calculated&#46; Topical AD treatments in the 6 months prior to the index date as well as selected concomitant treatments were extracted &#40;<a class="elsevierStyleCrossRef" href="#sec0085">Supplementary material Table 2</a>&#59; ATC codes<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">16</span></a>&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Systemic medications and phototherapy were obtained at the index date and throughout the follow-up period&#46; Lines of treatment were built &#40;Line 1&#44; Line 2&#44; Line 3 or Line<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#41;&#46; The first systemic treatment&#40;s&#41; or phototherapy initiated within the inclusion period &#40;index treatment or first line therapy&#41; prescribed in monotherapy or combination &#40;when more than one drug was prescribed on the same day&#41; were recorded&#46; For subsequent treatment lines combination was defined as the concomitant use of two or more systemic drugs or phototherapy&#46; Changes in the index or subsequent treatment lines include &#40;a&#41; discontinuation&#58; end of systemic treatment or phototherapy with the occurrence of a gap in a series of successive dispensations<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>60 days duration&#44; &#40;b&#41; switching&#58; end of systemic treatment or phototherapy with the start of a new systemic treatment within 60 days of the end of the prior treatment or &#40;c&#41; add-on&#58; start of a new systemic treatment or phototherapy while the prior treatment is still being prescribed&#46; Treatment duration for a specific drug was determined as the time &#40;days&#41; from initiation of that drug to the date of discontinuation or switching&#46; Continuous systemic treatment during the 3-year follow-up was defined as the lack of discontinuation of systemic treatment &#40;excluding oral corticosteroids&#41; within this time period <a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">HRU was described based on resources recorded during the 3-year follow-up period&#44; and used to calculate associated healthcare costs &#40;medical visits&#44; hospitalization days&#44; emergency visits&#44; diagnostic or therapeutic requests&#44; drug prescription&#41; and non-healthcare costs &#40;i&#46;e&#46;&#44; days on sick leave&#41;&#46; Only HRU associated with dermatological ICD-9-CM codes were considered for the analysis except for days of sick leave as they are not ICD-9-CM code linked&#46; Costs were expressed as an average cost per patient &#40;average&#47;unit&#41; per year&#44; as well as the total cost in the 3 years follow-up period&#46; Unit costs are detailed in <a class="elsevierStyleCrossRef" href="#sec0085">Supplementary material Table 3</a> &#40;year 2019&#41;&#46; The rates were obtained from the analytical accounting&#44; except for medication and days of sick leave&#46; The medical prescriptions were quantified according to the public retail price per pack at the time of prescription <a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">18</span></a>&#46; Days of sick leave were considered according to the average interprofessional salary <a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">19</span></a>&#46; This study did not consider direct non-healthcare costs paid by the patient&#47;family&#44; as they are not recorded in the database&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analyses</span><p id="par0070" class="elsevierStylePara elsevierViewall">Data were analyzed descriptively&#46; For categorical variables&#44; absolute and relative frequencies were provided&#46; Continuous variables were reported using means&#44; standard deviation &#40;SD&#41;&#44; median&#44; and the 25th and 75th percentiles of the distribution &#40;interquartile range&#41;&#46; Results are presented overall and by index treatment&#46; Where data were missing&#44; the number of missing values was provided&#46; The SPSSWIN program&#44; version 23&#44; was used for the analysis&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">Of 1&#44;867&#44;108 patients in the Big-Pac database&#44; 1995 were included in the analysis &#40;<a class="elsevierStyleCrossRef" href="#sec0085">Suppl&#46; Fig&#46; 1</a>&#41;&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Sociodemographic and clinical characteristics</span><p id="par0080" class="elsevierStylePara elsevierViewall">The mean &#40;SD&#41; age at index was 59&#46;8 &#40;17&#46;3&#41; years and 64&#46;4&#37; of patients &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1285&#41; were female&#46; Among those with available data &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1189&#41;&#44; the mean &#40;SD&#41; BMI was 29&#46;5 &#40;6&#46;0&#41; kg&#47;m<span class="elsevierStyleSup">2</span>&#46; The mean &#40;SD&#41; time from AD diagnosis was 23&#46;2 &#40;13&#46;4&#41; years&#44; 84&#37; with adult-onset AD&#46; The main comorbidities were general anxiety &#40;37&#46;9&#37;&#41;&#44; arterial hypertension &#40;35&#46;9&#37;&#41; and dyslipidemia &#40;35&#46;3&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Antibiotics&#44; antihistamines and antidepressants were present in 46&#46;8&#37;&#44; 29&#46;9&#37; and 26&#46;7&#37; of patients at the index date&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Treatment patterns</span><p id="par0085" class="elsevierStylePara elsevierViewall">The first systemic treatments or phototherapy that patients initiated at the index date &#40;i&#46;e&#46;&#44; Line 1&#41; were &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#58; oral corticosteroids &#40;83&#46;6&#37;&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1668&#41;&#44; immunosuppressants &#40;12&#46;8&#37;&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>256 mainly cyclosporine &#91;5&#46;3&#37;&#93; and methotrexate &#91;3&#46;9&#37;&#93;&#41;&#44; biological drugs &#40;0&#46;8&#37;&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41;&#44; other systemic drugs &#40;4&#46;3&#37;&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>86&#41; and phototherapy &#40;0&#46;2&#37;&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&#46; Most patients received these first systemic treatments in monotherapy &#40;98&#46;4&#37; vs 1&#46;7&#37; in combination&#44; being oral corticosteroids the main combination therapy&#41;&#46; The median &#40;IQR&#41; duration of first line therapies is presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Of the total number of patients included in the study &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1995&#41;&#44; 50&#46;7&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1011&#41;&#44; 11&#46;7&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>233&#41; and 3&#46;5&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&#41; required a second&#44; third or fourth systemic treatment line&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The mean &#40;SD&#41; number of lines of systemic treatment or phototherapy was 1&#46;7 &#40;0&#46;8&#41;&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#44; the use of oral corticosteroids remained high across the treatment lines &#40;83&#46;6&#37; in Line 1&#44; 86&#46;8&#37; in Line 2&#44; 74&#46;7&#37; in Line 3 and 84&#46;3&#37; in Lines<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#41;&#44; while immunosuppressants were more frequently used in later lines &#40;12&#46;8&#37; in Line 1&#44; 14&#46;5&#37; in Line 2&#44; 38&#46;6&#37; in Line 3&#44; and 30&#46;0&#37; in Lines<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#41;&#46; Biologics were more frequently used in Lines 2 &#40;11&#46;4&#37;&#41; and 3 &#40;13&#46;3&#37;&#41;&#46; The percentage of patients who received phototherapy was 11&#46;2&#37;&#46; During the 3-year follow-up period&#44; 12&#46;6&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>252&#41; of patients received systemic treatment continuously &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Treatment trajectories were heterogeneous &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Healthcare resource use and associated costs</span><p id="par0095" class="elsevierStylePara elsevierViewall">The mean &#40;SD&#41; annual cost per patient was &#8364;1278 &#40;&#8364;2079&#41;&#44; with the following cost components &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#58; &#8364;470 &#40;36&#46;8&#37;&#41; sick leave&#44; &#8364;200 &#40;15&#46;7&#37;&#41; specialist visits&#44; &#8364;187 &#40;14&#46;7&#37;&#41; hospitalization&#44; &#8364;167 &#40;13&#46;1&#37;&#41; medication&#44; &#8364;128 &#40;10&#46;0&#37;&#41; primary care visits&#44; &#8364;83 &#40;6&#46;5&#37;&#41; diagnostic therapeutic requests&#44; and &#8364;42 &#40;3&#46;3&#37;&#41; emergency room visits&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">The total cost per patient in the 3 years follow up was &#8364;3835 &#40;&#8364;6238&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">The Derma-Atopic Study characterized the clinical&#44; treatment and economic burden of AD in a real-world adult population treated with systemic drugs in Spain&#46; The study provides insights into the patterns of use of systemic treatments over a 3-year period in Spain&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">AD patients included in the study were predominantly female&#44; diagnosed in adulthood&#44; with an average of 60 years at systemic treatment initiation&#44; long disease duration and high comorbidity burden &#40;e&#46;g&#46;&#44; anxiety&#44; cardiovascular-related diseases&#41;&#46; Age at systemic treatment initiation was found to be consistent with other studies based on healthcare databases involving patients in primary and secondary care in Spain <a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">6&#44;13</span></a>&#44; and outside Spain <a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">20</span></a> By contrast&#44; patients selected for participation in primary data collection studies <a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">21&#44;22</span></a>&#44; where stricter age selection criteria were applied &#40;e&#46;g&#46;&#44; adults aged 18&#8211;65 years&#41;&#44; presented lower mean ages&#46; Coexisting AD-related comorbidities&#44; such as asthma and allergic rhinitis &#40;&#8216;atopic march&#8217;&#41;&#44; were present in approximately 16&#37; of patients in the current study&#46; This frequency was lower than that reported by Bruin Weller et al&#46;&#44; 2020 where a third of patients with moderate&#8211;severe disease also had asthma&#46; Concomitant treatments including antibiotics&#44; antihistamines and antidepressants&#44; were highly present in the study population highlighting the significant burden of AD symptoms &#40;e&#46;g&#46;&#44; itching&#41; and comorbidities&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Patients analyzed in the study presented considerable use of systemic treatments&#44; with more than half of them requiring at least two lines of treatment in the 3-year study period&#46; First line treatment was mostly based on short courses of oral corticosteroids&#44; which also remained consistently present across all treatment lines &#40;both in monotherapy and in combination&#41;&#46; The high use of oral corticosteroids versus other alternatives such as immunosuppressants&#44; may be explained by the contribution of patients from primary care practices in addition to secondary care&#44; where a higher use of immunosuppressants may be expected&#46; Patients who received immunosuppressants or biologics as first line&#44; remained on treatment for longer periods &#40;average of 117 and 331 days&#44; respectively&#41;&#46; The use of immunosuppressants &#40;mostly consisting of cyclosporine and methotrexate&#44; the latter used off-label&#41; increased as patients advanced in the treatment pathway&#44; in alignment with recommendations in current treatment guidelines<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">1</span></a>&#46; Interestingly&#44; although guidelines limit the use of intravenous immunoglobulin to children with refractory disease&#44; about 4&#37; of patients in the study and 20 of the 240 included patients in the Pereyra-Rodriguez<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">12</span></a> study reported the use of this treatment in adults&#46; As this study provides an overview of the AD treatment landscape between 2013 and 2019&#44; the use of dupilumab &#40;reimbursed in 2020 in Spain&#41;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">23</span></a> and that of other biologics &#40;off-label&#41; was scarce&#46; The availability of biological drugs and Janus kinase inhibitors &#40;JAKi&#41; is expected to result in a change of treatment paradigm in the moderate&#8211;severe AD setting<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">24</span></a>&#44; requiring further characterization of treatment pathways in the upcoming years&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Variability of clinical practice and treatment trajectories observed in the study confirms the heterogeneous nature of the disease which requires individualized treatment strategies in routine practice<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">13&#44;25&#44;26</span></a>&#46; About 20&#37; of patients in the study received systemic treatments continuously over a year and 13&#37; over a 3-year period&#46; These findings suggest that&#44; while some patients may present acute flare-driven disease requiring short term pharmacological interventions to relieve symptoms&#44; others develop a chronic disease course with persistent skin lesions and intense pruritus <a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">27</span></a>&#46; However&#44; the lack of data on severity scores&#44; patient-reported outcomes &#40;PROs&#41; and symptoms&#44; limited the interpretation of these results&#46; Additionally&#44; further research to describe the type of physicians initiating and prescribing systemic treatments &#40;e&#46;g&#46;&#44; general practitioner versus dermatologist&#41; and referral patterns for moderate&#8211;severe AD patients in the real world is warranted&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">AD poses a significant economic burden for the healthcare system&#44; patients and their families&#44; especially in its most severe forms<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">1&#44;2&#44;28</span></a>&#46; The present study estimated the cost of moderate&#8211;severe adult AD in &#8364;1278 per patient per year &#40;healthcare costs&#58; 63&#37;&#59; indirect costs&#58; 37&#37;&#41;&#46; A recent study conducted in Catalonia reported a higher unit cost&#44; which raised up to &#8364;3397 for severe and &#8364;2111 for moderate patients with a 75&#46;5&#37; for healthcare costs and 24&#46;5&#37; for indirect costs <a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">6</span></a>&#46; In both studies indirect costs based on productivity losses were heavily represented&#44; finding that aligns with existing evidence suggesting a significant impact of AD on work productivity <a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">29</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">This study presents some limitations&#46; The possible inaccuracy of the diagnostic coding for AD and other comorbidities&#44; or the lack of data on socio-economic level and clinical status&#44; contributing regions or hospitals which remain confidential&#44; therapeutic adherence&#44; phenotypes&#44; etc&#46; in the source database to further characterize the sample may constitute potential limitations of the study&#46; Also&#44; there may be an over representation of older AD cases in the study which may hinder comparison with studies using different data sources&#46; The validation and representativeness of the BIG-PAC database was previously explored&#44; however&#44; the analysis lacked socio-economic and educational level&#44; and the type of population covered &#40;urban&#47;rural&#41; <a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">15</span></a>&#46; While some uncertainty remains as to whether the results obtained in the present study can be generalized to the general population in Spain&#44; the published evidence using the BIG-PAC database indicates that it is appropriate to conduct studies in the real world setting for diverse conditions including AD in Spain<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">13&#44;30&#8211;33</span></a>&#46; Additionally&#44; the BIG-PAC database is registered in the ENCePP inventory as a data source eligible for conducting pharmacoepidemiology and pharmacovigilance studies in Europe&#46; Treatment and PROs and occurrence of flares were not recorded hindering the clinical interpretation of results&#46; The study attempted to select patients initiating a systemic drug or phototherapy for the first time to treat AD in their adult life&#39;s&#46; To that purpose&#44; patients with a prior record of systemic use or phototherapy in the 2 years prior to the index date were excluded&#46; However&#44; prior systemic use beyond those 2 years cannot be excluded&#46; Additionally&#44; costs were based on resources identified using proxies for AD-related in the absence of actual codes linked to each resource&#46; Therefore&#44; it is possible that some resource types are overestimated&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusions</span><p id="par0135" class="elsevierStylePara elsevierViewall">This study described a real-world population of adults with AD treated with systemic drugs in Spain&#46; Results suggest a high comorbidity and economic burden for the healthcare system&#44; patients and their families&#46; While variability in treatment patterns was observed&#44; short courses of oral corticosteroids remained as the main treatment option followed by immunosuppressants&#44; several used off-label&#46; This highlights the need for new systemic treatments indicated for use in AD&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">This study was funded by <span class="elsevierStyleGrantSponsor" id="gs1">Eli Lilly and Company</span>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">Esther Serra has received fees for acting as a scientific advisor and speaker for Eli Lilly and Company&#46; Esther Artime&#44; Silvia D&#237;az&#44; and Teresa Huete are employees of and minor shareholders in Eli Lilly and Company&#46; Ignacio Hern&#225;ndez&#44; Laura LLedo and Antoni Sicras are employees of and minor shareholders in Atrys Health S&#46;A&#46; in Spain&#46;</p></span></span>"
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              "identificador" => "abst0005"
              "titulo" => "Background"
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              "titulo" => "Methods"
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            0 => "Atopic dermatitis"
            1 => "Observational study"
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            3 => "Resource use"
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            0 => "Dermatitis at&#243;pica"
            1 => "Estudio observacional"
            2 => "Tratamientos sist&#233;micos"
            3 => "Uso de recursos"
            4 => "Costes sanitarios"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Moderate&#8211;severe atopic dermatitis &#40;AD&#41; has a significant impact on patients&#8217; lives&#44; with many requiring systemic treatment to manage symptoms &#40;e&#46;g&#46;&#44; pruritus&#41;&#46; Several drugs are used off-label to treat AD&#46; This study describes sociodemographic&#47;clinical characteristics&#44; treatment patterns&#44; health resource use &#40;HRU&#41; and costs in adults with AD who initiated systemic treatment or phototherapy in routine practice&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This retrospective observational study of electronic medical records in the BIG-PAC database identified adults with prior diagnosis of AD &#40;ICD-9&#58; 691&#46;8 or 692&#46;9&#41; starting oral corticosteroids&#44; immunosuppressants&#44; biologics or phototherapy between 01&#47;01&#47;2012 and 31&#47;12&#47;2016&#46; Patients were followed for 3 years from treatment initiation&#44; up to 31&#47;12&#47;2019&#46; Data on patient characteristics&#44; treatment patterns&#44; HRU and costs were analyzed descriptively&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patients &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1995&#41; had a mean age of 60 years&#44; 64&#37; were female&#44; with a mean time of 23 years since diagnosis &#40;84&#37; were &#8805;18 years at AD onset&#41;&#46; Main comorbidities were anxiety &#40;38&#37;&#41;&#44; arterial hypertension &#40;36&#37;&#41; and dyslipidemia &#40;35&#37;&#41;&#46; Most patients used oral corticosteroids as first systemic &#40;84&#37;&#59; median duration 29 days&#41; and immunosuppressants in 13&#37; of patients &#40;median duration 117 days&#44; 5&#37; cyclosporine and 4&#37; methotrexate&#41;&#46; Half of patients required a second line systemic and 12&#37; a third line&#46; The use of immunosuppressants and biologics increased with treatment lines&#46; About 13&#37; of patients received systemic treatments continuously over the 3-year follow-up&#46; The average 3-year per patient cost was 3835 euros&#44; with an average annual cost of 1278 euros&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Results suggest a high comorbidity and economic burden in this real-world adult population with AD&#44; and the need for systemic treatments indicated for use in AD&#46;</p></span>"
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          0 => array:2 [
            "identificador" => "abst0005"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La dermatitis at&#243;pica &#40;DA&#41; moderada-grave tiene un impacto significativo en la vida de los pacientes&#44; muchos de los cuales requieren tratamiento sist&#233;mico para controlar los s&#237;ntomas &#40;p&#46; ej&#46;&#44; prurito&#41;&#46; Algunos tratamientos son usados fuera de indicaci&#243;n&#46; Este estudio describi&#243; caracter&#237;sticas sociodemogr&#225;ficas y cl&#237;nicas&#44; patrones de tratamiento&#44; uso de recursos sanitarios &#40;URS&#41; y costes asociados en adultos con DA que iniciaron tratamiento sist&#233;mico o fototerapia en la pr&#225;ctica habitual&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Este estudio observacional retrospectivo de historias cl&#237;nicas electr&#243;nicas en la base de datos BIG-PAC identific&#243; adultos con diagn&#243;stico previo de DA &#40;CIE-9&#58; 691&#46;8 o 692&#46;9&#41; que comenzaron con corticosteroides orales&#44; inmunosupresores&#44; biol&#243;gicos o fototerapia entre el 01&#47;01&#47;2012 y el 31&#47;12&#47;2016&#46; Se sigui&#243; a los pacientes durante 3 a&#241;os desde el inicio del tratamiento&#44; hasta 31&#47;12&#47;2019&#46; Los datos sobre las caracter&#237;sticas cl&#237;nicas de los pacientes&#44; patrones de tratamiento&#44; URS y costes se analizaron de forma descriptiva&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los pacientes &#40;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1995&#41; ten&#237;an una edad media de 60 a&#241;os&#44; el 64&#37; eran mujeres&#44; con una media de 23 a&#241;os desde el diagn&#243;stico &#40;84&#37; ten&#237;an<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>18 a&#241;os al inicio de la DA&#41;&#46; Las principales comorbilidades fueron ansiedad &#40;38&#37;&#41;&#44; hipertensi&#243;n arterial &#40;36&#37;&#41; y dislipidemia &#40;35&#37;&#41;&#46; La mayor&#237;a de los pacientes utilizaron corticosteroides orales como primer tratamiento sist&#233;mico &#40;84&#37;&#59; duraci&#243;n media 29 d&#237;as&#41; e inmunosupresores en el 13&#37; de los pacientes &#40;duraci&#243;n media 117 d&#237;as&#44; ciclosporina en el 5&#37; y metotrexato en el 4&#37;&#41;&#46; La mitad de los pacientes requirieron una segunda l&#237;nea de tratamiento sist&#233;mico y el 12&#37; una tercera&#46; El uso de inmunosupresores y biol&#243;gicos aument&#243; simult&#225;neamente con las l&#237;neas de tratamiento&#46; Aproximadamente el 13&#37; de los pacientes recibieron tratamientos sist&#233;micos de forma continua durante los 3 a&#241;os de seguimiento&#46; El coste medio por paciente a 3 a&#241;os fue de 3&#46;835 euros&#44; con un coste medio anual de 1&#46;278 euros&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados sugieren una alta carga econ&#243;mica y de comorbilidad en esta poblaci&#243;n del mundo real de adultos con DA&#44; y la necesidad de nuevos tratamientos sist&#233;micos indicados para DA&#46;</p></span>"
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            "titulo" => "M&#233;todos"
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            "apendice" => "<p id="par0155" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0085"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Illustration of study design&#46;</p>"
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        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Comorbidities at&#47;before the index date &#40;frequency &#8805;5&#37;&#41;&#46;</p>"
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        "etiqueta" => "Figure 3"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Systemic treatments&#47;phototherapy initiated at the index date&#46;</p>"
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        "etiqueta" => "Figure 4"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Lines of systemic treatment&#47;phototherapy in the 3-year follow-up period&#46;</p>"
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        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Sequence of lines of systemic treatment&#47;phototherapy&#46;</p>"
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        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
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            "imagen" => "gr6.jpeg"
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            "Tamanyo" => 167761
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Components of the annual per patient cost&#46;</p>"
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                  \t\t\t\t">59&#46;8 &#40;17&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>18&#8211;44 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>45&#8211;64 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;65 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">893 &#40;44&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1285 &#40;64&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time from AD diagnosis &#40;mean SD&#41;&#44; years</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">8&#46;8 &#40;1&#46;3&#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="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#60;14 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142 &#40;7&#46;1&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>14&#8211;17 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">177 &#40;8&#46;9&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>18&#8211;60 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1445 &#40;72&#46;4&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;60 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">231 &#40;11&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;5 &#40;6&#46;0&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;5 &#40;1&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Non-systemic treatments in the 6 months prior to the index date&#44;</span><span class="elsevierStyleItalic">n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Topical corticosteroids&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">629 &#40;31&#46;5&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Topical immunomodulators&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;1&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant treatments at the index date&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Antihistamines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">596 &#40;29&#46;9&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Antibiotics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">933 &#40;46&#46;8&#37;&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Antidepressants&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">528 &#40;26&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1668&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">29&#46;0 &#40;8&#46;8&#8211;53&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&#46;5 &#40;49&#46;0&#8211;286&#46;0&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cyclosporine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">106&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86&#46;0 &#40;33&#46;0&#8211;236&#46;0&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Azathioprine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&#46;0 &#40;43&#46;0&#8211;330&#46;5&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mycophenolate mofetil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">242&#46;0 &#40;50&#46;0&#8211;784&#46;0&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">133&#46;0 &#40;83&#46;0&#8211;387&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Biologics</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">331&#46;0 &#40;277&#46;5&#8211;430&#46;0&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dupilumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Line 1<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1995&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Number of lines &#40;mean&#44; SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Number of systemic treatment classes received&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1 systemic&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>2 systemics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;2 systemics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">234 &#40;11&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Line 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1011 &#40;50&#46;7&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Line 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">233 &#40;11&#46;7&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;3 Lines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">70 &#40;3&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Number of patients on continuous systemic treatment excluding oral corticosteroids&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>First year&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">374 &#40;18&#46;8&#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="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>First 2 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">334 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Specialist visits&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;7 &#40;4&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;1 &#40;13&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hospitalization&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Medication&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8364;167 &#40;&#8364;732&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#8364;501 &#40;&#8364;2197&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Primary care visits&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;5 &#40;3&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8364;128 &#40;&#8364;72&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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