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            "identificador" => "aff0060"
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        "titulo" => "Manejo de los efectos adversos de apremilast desde un abordaje multidisciplinar"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0155" class="elsevierStylePara elsevierViewall">Since its approval by the European Commission in 2015&#44; apremilast has been used in the treatment of psoriasis and psoriatic arthritis in adult patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;5</span></a> The agent is an oral inhibitor of phosphodiesterase 4 &#40;PDE-4&#41; and has a good safety profile with a low incidence of adverse effects&#59; those that do occur are mainly of mild or moderate severity and largely involve the digestive tract&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> The incidence of these adverse effects is higher during the first 2 months of treatment and then decreases notably&#44; particularly from the second year of use onwards &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> They often resolve without need for medical intervention or dose adjustment&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Although the rate of treatment discontinuations due to adverse effects was less than 2&#37; during clinical development&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> a higher rate of apremilast discontinuations has been reported in clinical practice &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">In order to assess the strategies available for management of adverse effects that most often lead to treatment discontinuation in patients with psoriasis and&#47;or psoriatic arthritis &#40;diarrhea&#44; nauseas&#44; and headache&#41;&#44; a multidisciplinary committee of experts in rheumatology&#44; dermatology&#44; neurology&#44; gastroenterology&#44; hospital pharmacy&#44; and nursing&#44; belonging to 14 Spanish hospitals&#44; conducted a broad review of the literature&#44; with special focus on the general pathophysiology of each adverse effect from the point of view of their particular specialty&#46; After considering this information and personal experience&#44; a series of consensus recommendations were made&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Headache</span><p id="par0165" class="elsevierStylePara elsevierViewall">Drug-induced headaches are a neurological process triggered by activation of pain-modulating structures in the central or peripheral nervous system&#46; A migraine attack can be triggered through action on different structures involved in its pathophysiology or by altering the antinociceptive structures that are responsible for migraine resolution&#46; In the framework of pathophysiology of migraines&#44; in recent years&#44; the importance of neuropeptides that participate in genesis of pain and other typical symptoms of migraine has been increasingly recognized&#46; Release of neuropeptides leads to nerve fiber sensitization &#40;neuronal hyperexcitability&#41;&#44; thereby enhancing central and peripheral pain and inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Calcitonin gene-related peptide &#40;CGRP&#41;&#44; pituitary adenylate cyclase-activating peptide &#40;PACAP&#41;&#44; and their respective receptors are one of the main targets for new migraine therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Although the mechanism that triggers headache after administration of PDE-4 inhibitors has not been elucidated&#44; it could be related to release of peptides that induce symptoms similar to migraine&#46; The participation of PACAP and other neuropeptides could be responsible for the appearance of these symptoms&#44; such that we might be facing 2 situations&#58; 1&#41; patients with migraine who see their pain exacerbated&#44; whether in intensity or frequency&#44; and 2&#41; patients who have had not suffered from headache and who start with a throbbing headache with sensitization &#40;pathophysiology similar to migraine&#41; or a headache with a different profile&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients With History of Headache Before Treatment With Apremilast</span><p id="par0175" class="elsevierStylePara elsevierViewall">For patients with a history of migraine&#44; there is the option of administering preventive treatment 2 weeks before starting apremilast therapy&#44; as later administration may lead to a delay in the resolution of symptoms&#46; Melatonin&#44; at a dose of 3&#8239;mg&#47;mg&#44; could be a good option for preventive treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> with triptanes as an option in the event of a migraine attack &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Sumatriptan&#44; at a dose of 25&#8211;100&#8239;mg&#47;day&#44; is indicated for acute treatment of intermittent migraine&#44; with or without aura&#46; If the patient responds after the first dose&#44; and symptoms recur&#44; a second dose could be administered in the following 24&#8239;h if more than 2&#8239;h have elapsed since the first dose &#40;maximum 300&#8239;mg&#47;day&#41;&#46; Adverse effects that have been reported frequently for sumatriptan include general disorders &#40;weakness&#44; fatigue&#44; pressure&#41; and musculoskeletal disorders &#40;heaviness&#44; myalgia&#41;&#44; which are generally transient and of mild or moderate intensity&#46; Other reactions include dyspnea&#44; increased blood pressure&#44; dizziness&#44; somnolence&#44; and sensory abnormalities&#46; In the event of lack of response to sumatriptan&#44; treatment with paracetamol or nonsteroidal anti-inflammatory drugs &#40;NSAIDs&#41; is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">Alternatively&#44; other preventive therapies include amitriptyline or beta-blockers&#44; depending on the profile of the patient&#46; The initial recommended dose of amitriptyline is 10&#8211;25&#8239;mg&#44; before going to bed&#44; with an increase of 10&#8211;25&#8239;mg every 3&#8211;7 days&#44; depending on the tolerance of the patient &#40;maximum 25&#8211;75&#8239;mg&#47;day&#41;&#46; The analgesic effect is usually felt after 2&#8211;4 weeks of treatment&#44; and the most frequent adverse effects include&#58; aggression&#44; somnolence&#44; dizziness&#44; headache&#44; blurry vision&#44; palpitations&#44; tachycardia&#44; constipation&#44; nausea&#44; dry mouth&#44; weight gain&#44; nasal congestion&#44; hyperhidrosis&#44; and orthostatic hypotension&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Of the beta-blockers&#44; propranolol is indicated for prophylactic treatment of migraine with an initial dose of 40&#8239;mg 2 or 3 times a day&#44; with increments by the same amount over weekly intervals depending on the response of the patient up to 80&#8211;160&#8239;mg&#47;day &#40;maximum 240&#8239;mg&#47;day&#41;&#46; It should be remembered that administration of propranolol may cause fatigue&#44; bradycardia&#44; cold hands and feet&#44; Raynaud phenomenon&#44; and sleep disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> It should also be remembered that beta-blockers&#44; and propranolol in particular&#44; belong to the group of drugs able to induce or exacerbate psoriasis&#46; A careful assessment of the benefit&#47;risk profile is therefore important prior to recommending its use&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Patients With Headache That Presents After Starting Treatment With Apremilast</span><p id="par0185" class="elsevierStylePara elsevierViewall">In patients who present with headache after administration of apremilast&#44; 3 differential characteristics of the type of headache should be considered&#58; 1&#41; the throbbing component&#59; 2&#41; whether it worsens with activity and&#47;or head movement&#59; and 3&#41; if photophobia is present &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The presence of these 3 components corresponds to a profile of meningeal inflammation denoted migraine type&#46; Therapeutic intervention is only necessary when the headaches have an impact on the quality of life of the patient&#46; In this case&#44; treatment for this type of headache is based on administration of NSAIDs&#44; such as for example naproxen and ibuprofen&#44; or triptanes &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; As a general regimen&#44; daily doses of naproxen range from 550&#8239;mg to 1&#46;1&#8239;g&#44; with a recommended starting dose of 550&#8239;mg followed by 275&#8239;mg every 6&#8211;8&#8239;h&#44; depending on the intensity of the headache&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The daily recommended dose of ibuprofen is 1&#46;2&#8211;1&#46;8&#8239;g&#44; administered over several doses and without exceeding a dose of 2&#46;4&#8239;mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In contrast&#44; if the headache is of the tension type&#44; treatment with paracetamol or metamizole is recommended&#44; with the additional use of an NSAID also an option&#46; A regimen of 500&#8239;mg of paracetamol every 4&#8211;6&#8239;h or 1&#8239;g every 8&#8239;h is recommended&#44; without exceeding the maximum dose of 3&#8239;g&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Metamizole can be administered at a dose of 575&#8239;mg &#40;a capsule&#41; 3 or 4 times a day for a week&#44; without exceding the maximum dose of 6 capsules&#47;day&#46; Reactions of hypotension can present during or after treatment with metaizol&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diarrhea</span><p id="par0190" class="elsevierStylePara elsevierViewall">Diarrhea caused by PDE-4 inhibitors is considered of a secretory nature&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The increase in intracellular cAMP caused by PDE-4 inhibition can trigger intestinal secretion through activation of chlorine channels in the apical membrane of the enterocytes and inhibition of NaCl absorption&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;19</span></a> Different isoforms of PDE-4 interact with the cystic fibrosis transmembrane conductance regulator &#40;CFTR&#41;&#44; a chlorine channel implicated in secretion and homeostasis&#44; whose hyperactivation may give rise to secretory diarrhea&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Through protein kinase A &#40;PKA&#41;&#44; cAMP also promotes intestinal secretion by activation of different membrane proteins in the enterocytes&#44; such as K<span class="elsevierStyleSup">&#43;</span> and anion channels and NaK<span class="elsevierStyleInf">2</span>Cl transporters&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In addition&#44; it has been suggested that early resolution of symptoms associated with diarrhea caused by apremilast &#40;in approximately 2 weeks&#41; could be due to upregulation of other PDEs in the intestine&#44; as a compensatory mechanism for PDE-4 inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">As described for headache&#44; the best strategy for appropriate management of gastrointestinal adverse effects&#44; when considered necessary&#44; is to administer a treatment that is thought to act effectively on the underlying pathophysiology&#46; Preventive measures such as administration of apremilast during meals&#44; avoiding excessive liquid intake or intake of caffeine and sweeteners could reduce or delay the onset of symptoms of secretory diarrhea caused by apremilast&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Although not fully accepted&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> it is possible that administration of probiotics could reduce the symptoms associated with gastrointestinal intolerance&#44; thus permitting better therapeutic compliance and a lower discontinuation rate&#46; On the other hand&#44; fiber supplements and administration of bismuth subsalicylate may be used as a complementary therapy to reduce water loss and the number of depositions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In any case&#44; it is recommended to follow a simple treatment regimen that is not accompanied by major changes in the patient&#8217;s lifestyle&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Apremilast-induced diarrhea is usually self-limiting and resolves in the first few weeks of treatment&#46; If pharmacological intervention is deemed necessary&#44; secretory diarrhea could be treated effectively with racecadotril&#44; an antisecretory agent that can be used for the treatment of apremilast-induced diarrhea &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Racecadotril acts by inhibiting intestinal encephalinase&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> thus reducing water and electrolyte secretion to the intestinal lumen&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Administration of 100&#8239;mg every 8&#8239;h&#44; preferably before meals&#44; has been shown to shorten the duration of diarrhea symptoms&#44; reduce the number of depositions&#44; and reduce the need for rehydration&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> This regimen is recommended to continue for 7 days&#44; until attaining 2 depositions&#47;day&#46; Adverse skin reactions&#44; generally moderate&#44; have been reported&#44; along with headache and cases of hypersensitivity&#47;angioneurotic edema in patients in treatment with racecadotril&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Other pharmacological options for the treatment of diarrhea caused by apremilast include loperamide and codeine&#46; Loperamide is indicated for treatment of acute diarrhea with an initial dose of 4&#8239;mg &#40;2 tablets&#41;&#44; continuing with 1 tablet after each deposition&#44; for a maximum of 2 days and 4 tablets&#47;day&#46; Gastrointestinal disorders &#40;nausea and dysgeusia&#41; have often been reported after treatment with loperamide&#46; If clinical improvement is not observed in 48&#8239;h&#44; or if symptoms of constipation&#44; ileus&#44; or abdominal distension appear&#44; administration of loperamide should be discontinued&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In the case of treatment with codeine&#44; the recommended regimen is 1 tablet &#40;21&#46;4&#8239;mg&#41; every 6&#8239;h&#59; this can be increased to 2 tablets per administration&#44; for a maximum duration of 2 days&#44; administering 6 tablets&#47;day&#46; Administration of codeine can cause somnolence and alcohol intake should be avoided during treatment&#44; as this can enhance the depressor effect on the CNS&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Nausea</span><p id="par0205" class="elsevierStylePara elsevierViewall">Nausea induced by PDE-4 inhibitors appears to be triggered by central and peripheral mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;29</span></a> This adverse effect has been associated with lack of selectivity of PDE-4 inhibitors for the different isoforms &#40;A&#44; B&#44; C&#44; D&#41; expressed in different cell types&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> Specifically&#44; the PDE-4 D isoform is expressed in neurons of the area postrema&#44; where the chemoreceptor trigger zone that links with the vomit center is located&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The increase in intracellular levels of cAMP in neurons of the area postrema ultimately triggers the emetic response&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> While apremilast has been reported to be highly specific for PDE-4&#44; it has a similar potency for each of the different isoforms of this enzyme&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;31&#44;32</span></a> The lack of selectivity for the PED-4 isoform could explain the improved therapeutic index of apremilast in in vivo models compared with other PDE-4 inhibitors for gastrointestinal adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Among these nonpharmacological interventions&#44; frequent smaller meals as well as limited liquid intake during meals may help reduce the sensation of nausea&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> As with the preventive measures for diarrhea&#44; a simple and personalized approach is recommended according to the patient&#8217;s characteristics&#44; without limiting his or her quality of life&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Ondansetron is a potent and highly selective serotonergic 5HT<span class="elsevierStyleInf">3</span> antagonist that blocks the vomiting reflex at both the central and peripheral level&#46; It is therefore indicated for controlling nausea and vomiting following surgery or induced by radiotherapy or cytotoxic chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Given its high efficacy as an antiemetic and its good tolerability&#44; ondansetron could be considered a good pharmacological option for treatment of nausea that persists during treatment with apremilast &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Ondansetron can be administered orally or intravenously&#44; with the oral regimen being 8&#8239;mg between 1 or 2&#8239;h prior to emetogenic treatment&#44; followed by 8&#8239;mg every 12&#8239;h for up to a maximum of 5 days&#46; The most frequently reported adverse effects are headache&#44; burning sensation &#40;hot flushes&#41;&#44; and constipation&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> It should be remembered that ondansetron is not currently reimbursed under the Spanish National Health System&#44; and so its use would require an off-label request&#46; Alternatively&#44; metoclopramide could be used&#46; This is a neuroleptic agent with antiemetic properties used for prevention and symptomatic treatment of nausea and vomiting&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> A single dose of 10&#8239;mg of metoclopramide is recommended&#46; This dose can be repeated up to 3 times a day&#44; with at least 6&#8239;h between dosing &#40;even in the case of vomiting or dose rejection&#41; up to maximum duration of 5 days&#46; During treatment with metoclopramide&#44; particularly when used at high doses&#44; adverse effects such as diarrhea&#44; asthenia&#44; somnolence&#44; extrapyramidal disorders&#44; parkinsonism&#44; akathisia&#44; depression&#44; and hypotension may appear&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0220" class="elsevierStylePara elsevierViewall">The possibility should also be considered that nausea is not a direct result of apremilast treatment but rather a side effect of the neurological adverse effects described above&#46; It is therefore recommended to evaluate each case individually&#44; and tailor management of the adverse effect that has triggered the symptoms in the first place&#46; Metoclopramide is also indicated for the treatment of nausea and vomiting induced by acute migraine&#44; and can be administered in combination with oral analgesics to improve absorption of these analgesics&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">General Recommendations</span><p id="par0225" class="elsevierStylePara elsevierViewall">Taking into consideration the above&#44; a series of general recommendations are derived to facilitate the prevention and management of possible adverse effects caused by apremilast in clinical practice &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0230" class="elsevierStylePara elsevierViewall">Adverse effects caused by apremilast should be managed in a multidisciplinary setting&#46; Optimization of their management would no doubt be of clinical benefit to patients affected by these adverse effects&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of Interest</span><p id="par0235" class="elsevierStylePara elsevierViewall">Esteban Daud&#233;n&#58; advisory board member&#44; consultant&#44; grant recipient&#44; research support&#44; participation in clinical trials&#44; speaker fees with the following pharmaceutical companies&#58; Abbott&#47;AbbVie&#44; Almirall&#44; Amgen&#44; Biogen&#44; Celgene&#44; Janssen-Cilag&#44; Leo Pharma&#44; Lilly&#44; MSD&#44; Novartis&#44; and Pfizer&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Jorge Alonso Su&#225;rez&#58; advisory board member&#44; consultant&#44; grant recipient&#44; research support&#44; participation in clinical trials&#44; speaker fees with the following pharmaceutical companies&#58; AbbVie&#44; Almirall&#44; Janssen-Cilag&#44; Leo Pharma&#44; Novartis&#44; Pfizer&#44; Celgene&#44; Lilly&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">M&#46; Carmen Herrero Manso&#58; consultancy&#44; courses&#44; book chapters&#44; or congress attendance with UCB Pharma&#44; Celgene&#44; MSD&#44; Pfizer&#44; Mylan&#44; BMS&#44; AbbVie&#44; Janssen&#44; Sandoz&#44; Gedeon Richter&#44; Novartis&#44; Lilly&#44; Gebro&#44; Nordic&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Ignacio Mar&#237;n-Jim&#233;nez&#58; consultancy&#44; support for investigations or congress attendance with&#58; AbbVie&#44; Amgen&#44; Celgene&#44; Dr&#46; Falk Pharma&#44; Faes Farma&#44; Ferring&#44; Fresenius&#44; Janssen&#44; MSD&#44; Pfizer&#44; Sandoz&#44; Takeda&#44; and UCB-Pharma&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">M&#46; Dolores Mart&#237;n-Arranz&#58; Advisory Board member and support for investigation with the following pharmaceutical companies&#58; MSD&#44; AbbVie&#44; Hospira&#44; Pfizer&#44; Takeda&#44; Janssen&#44; Shire Pharmaceuticals&#44; Tillotts Pharma&#44; Faes Farma&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Miguel A&#46; Rodr&#237;guez-Sagrado&#58; renumerated activities for AbbVie&#44; Biogen&#44; Celgene&#44; Gilead&#44; Intercept&#44; Janssen&#44; Merck-Serono&#44; MSD&#44; Novartis&#44; Roche&#44; Sandoz&#44; Tesaro&#44; and ViiV&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Jos&#233; Rosas G&#243;mez de Salazar&#58; Advisory Board member&#58; AbbVie&#44; Celgene&#44; Grifols&#44; Janssen&#44; Lilly&#44; Pfizer&#46; Speakers fees&#58; Amgen&#44; Grifols&#44; Janssen&#44; Lilly&#44; MSD&#44; Novartis&#44; Pfizer&#44; Stada</p><p id="par0270" class="elsevierStylePara elsevierViewall">Laura Salgado-Boquete&#58; advisory board member&#44; consultant&#44; grant recipient&#44; research support&#44; participation in clinical trials&#44; speaker fees from the following pharmaceutical companies&#58; AbbVie&#44; Almirall&#44; Janssen-Cilag&#44; Leo Pharma&#44; Novartis&#44; Pfizer&#44; MSD-Schering-Plough&#44; Celgene&#44; Lilly&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">The remaining authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Headache"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Patients With History of Headache Before Treatment With Apremilast"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Patients With Headache That Presents After Starting Treatment With Apremilast"
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          "titulo" => "Diarrhea"
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          "titulo" => "General Recommendations"
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        11 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2020-04-09"
    "fechaAceptado" => "2020-08-22"
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            0 => "Apremilast"
            1 => "Psoriasis"
            2 => "Headache"
            3 => "Diarrhea"
            4 => "Nausea"
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            0 => "Apremilast"
            1 => "Psoriasis"
            2 => "Cefalea"
            3 => "Diarrea"
            4 => "N&#225;useas"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">We present a series of general and specific recommendations based on pathophysiologic considerations for managing the most common adverse effects of apremilast that lead to treatment discontinuation&#58; diarrhea&#44; nausea&#44; and headache&#46; The recommendations are based on a review of the literature and the experience of a multidisciplinary team of 14 experts including dermatologists&#44; rheumatologists&#44; neurologists&#44; gastroenterologists&#44; pharmacists&#44; and nurses&#46; We propose a series of simple algorithms that include clinical actions and suggestions for pharmacologic treatment&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">The adverse effects of apremilast can be managed from a multidisciplinary approach&#46; The purpose of optimizing management is to bring clinical benefits to patients&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">En el presente art&#237;culo&#44; en base a una revisi&#243;n de la literatura y su experiencia personal&#44; un equipo multidisciplinar de 14 profesionales sanitarios &#40;incluyendo dermat&#243;logos&#44; reumat&#243;logos&#44; neur&#243;logos&#44; gastroenter&#243;logos&#44; farmac&#233;uticos y enfermeras&#41; ha elaborado una serie de recomendaciones generales y espec&#237;ficas &#40;basadas en la fisiopatolog&#237;a&#41; para el manejo de los efectos adversos secundarios a apremilast que con mayor frecuencia conducen a la suspensi&#243;n del tratamiento &#40;diarrea&#44; n&#225;useas y cefalea&#41;&#46; Se aportan algoritmos sencillos de manejo que incluyen aspectos cl&#237;nicos de evaluaci&#243;n y sugerencias de tratamiento farmacol&#243;gico&#46;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Los efectos adversos de apremilast pueden ser abordados desde un punto de vista multidisciplinar y la optimizaci&#243;n en su manejo pretende proporcionar un beneficio cl&#237;nico a los pacientes que los sufren&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Daud&#233;n Tello E&#44; Alonso Su&#225;rez J&#44; Beltr&#225;n Catal&#225;n E&#44; Blasco Maldonado C&#44; Herrero Manso MC&#44; Jim&#233;nez Morales A&#44; et al&#46; Manejo de los efectos adversos de apremilast desde un abordaje multidisciplinar&#46; Actas Dermosifiliogr&#46; 2021&#59;112&#58;134&#8211;141&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Algorithm for management of headache induced by apremilast&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">&#42;As an alternative to these treatments&#44; lengthening the initial escalation regimen of apremilast by 1&#8211;2&#8239;weeks and&#47;or lowering the dose &#40;30&#8239;mg&#47;day&#41; can be considered&#46; This strategy may help lower the rate of headache observed in the early phases of treatment&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Algorithm for management of diarrhea induced by apremilast&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">&#42;As an alternative to these treatments&#44; lengthening the initial escalation regimen of apremilast by 1&#8211;2&#8239;weeks and&#47;or lowering the dose &#40;30&#8239;mg&#47;day&#41; can be considered&#46; This strategy may help lower the rate of diarrhea observed in the early phases of treatment&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Algorithm for management of nausea induced by apremilast&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">&#42;As an alternative to these treatments&#44; lengthening the initial escalation regimen of apremilast by 1&#8211;2&#8239;weeks and&#47;or lowering the dose &#40;30&#8239;mg&#47;day&#41; can be considered&#46; This strategy may help lower the rate of nausea observed in the early phases of treatment&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">General recommendations for educating the patient and managing adverse effects caused by apremilast&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; NE&#44; not evaluated&#59; PsA&#44; psoriatic arthritis&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Adapted from Crowley et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and Kavanaugh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p>"
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                0 => """
                  <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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 1&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 2&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 3&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 4&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 5&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diarrhea</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nausea</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;4&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\ttop\n
                  \t\t\t\t">3&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tension headache</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; CP&#44; clinical practice&#59; CT&#44; combined analysis of clinical trials&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Adapted from Ighani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p>"
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                0 => """
                  <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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diarrhea&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Frequency of adverse effect&#44; &#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CT&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;1&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CP&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;4&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;9&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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment discontinuation&#44; &#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CT&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
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                  \t\t\t\t">1&#46;6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;6&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CP&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;3&nbsp;\t\t\t\t\t\t\n
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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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prior Considerations&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Preventive Treatment&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" style="border-bottom: 2px solid black">Pharmacological Treatment&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</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Only in case of headache prior to treatment</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Migraine type</span>&#58;&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 " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Patients with history of headache before starting apremilast treatment</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">Melatonin&#58; 3&#8239;mg&#47;day</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">Amitriptyline&#58; 10&#8722;25&#8239;mg&#47;day with increase every 3&#8722;7&#8239;d &#40;maximum 25&#8722;75&#8239;mg&#47;day&#41;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Beta-blockers<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#58; propranolol 40&#8239;mg 2&#8211;3&#8239;times&#47;day with weekly increase to 80&#8722;160&#8239;mg&#47;day &#40;maximum 240&#8239;mg&#47;day&#41;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0020" class="elsevierStylePara elsevierViewall">Triptanes &#40;in case of migraine attack&#41;&#58; sumatriptan 25&#8722;100&#8239;mg&#47;day</p></li></ul></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">NSAID&#58; naproxen 550&#8239;mg&#8239;&#43;&#8239;275&#8239;mg every 6&#8722;8&#8239;h&#59; ibuprofen 1&#46;2&#8722;1&#46;8&#8239;g&#47;day in several doses</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Triptanes&#58; sumatriptan 25&#8722;100&#8239;mg&#47;day</p></li></ul>&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tension type</span>&#58;&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Paracetamol&#58; 500&#8239;mg every 4&#8722;6&#8239;h or 1&#8239;g every 8&#8239;h</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Metamizole&#58; 575&#8239;mg 3&#8722;4&#8239;times&#47;day &#40;maximum 7&#8239;days&#41;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">NSAID&#58; naproxen 550&#8239;mg &#43;&#8239;275&#8239;mg every 6&#8722;8&#8239;h&#59; ibuprofen 1&#46;2&#8722;1&#46;8&#8239;g&#47;day in several doses</p></li></ul>&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="elsevierStyleItalic">Diarrhea</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Frequent smaller meals</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Limit liquid intake during meals</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Consider avoiding dairy products&#44; caffeine&#44; and artificial sweeteners</p></li></ul>&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="left" valign="\n
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                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Racecadotril&#58; 100&#8239;mg every 4&#8722;6&#8239;h for 7&#8239;days</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Loperamide&#58; 2 tablets &#40;4&#8239;mg&#41; and then 1 after every deposition &#40;maximum 4&#8239;tablets&#47;day for 2&#8239;days&#41;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Codeine&#58; 1&#8722;2 tablets &#40;21&#46;4&#8239;mg&#47;tablet&#41; every 6&#8239;h &#40;maximum 6 tablets&#47;day for 3&#8239;days&#41;</p></li></ul>&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="elsevierStyleItalic">Nausea</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  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Frequent smaller meals</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Limit liquid intake during meals</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Avoid activity after eating</p></li></ul></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Ondansetron&#58; 8&#8239;mg before first apremilast treatment and then every 12&#8239;h</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Metoclopramide&#58; 10&#8239;mg&#44; 3&#8239;times&#47;day</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">For a maximum of 5 days</p></li></ul></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>Relationship with headache caused by apremilast treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Management of Headache&#44; Diarrhea&#44; and Nausea Caused by Apremilast Treatment&#46;</p>"
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      7 => array:8 [
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        "etiqueta" => "Table 4"
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                  <table border="0" frame="\n
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                  \t\t\t\t" class=""><tbody title="tbody"><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"><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">The onset of adverse effects caused by apremilast therapy usually occurs in the first 2&#8722;4&#8239;weeks of treatment&#44; and they are usually self-limiting and resolve spontaneously in the initial phases of treatment</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">If pharmacological treatment is required and if the diarrhea&#44; nausea&#44; or headache persist despite treatment&#44; negatively impacting the patient&#8217;s quality of life&#44; the options of referring him or her to the gastroenterology or neurology department could be considered</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">The decision to refer the patient to another department and&#47;or discontinue treatment with apremilast should be taken on an individual basis&#44; taking into account the expectations of apremilast treatment compared with other available drugs&#44; as well as the delay at each center in obtaining multidisciplinary care or care in another department</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">As an alternative to the treatments considered above&#44; lengthening the initial apremilast escalation regimen by 1&#8722;2&#8239;weeks and&#47;or using lower doses &#40;30&#8239;mg&#47;day&#41; could help reduce adverse effects that develop in early phases of treatment</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">With the aim of avoiding early discontinuation of treatment by the patient&#44; it is recommended to provide him or her with sufficient information on the possible adverse effects &#40;type&#44; estimated duration&#44; and treatment&#41; before starting therapy with apremilast</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Performing a follow-up visit at 1 month after starting therapy helps minimize and promptly resolve adverse effects&#44; improving the patient&#8217;s therapeutic compliance</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8226;</span><p id="par0140" class="elsevierStylePara elsevierViewall">An appropriate communication system &#40;telephone contact&#44; nursing visit&#44; support service&#44; etc&#46;&#41; will help the patient have ready access to health care professionals to resolve doubts about management of possible adverse effects</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">It is recommended that the patient is sufficiently well informed and is provided with the prophylactic and therapeutic options available before discontinuing treatment</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Both the management of adverse effects and patient education can be performed in a multidisciplinary setting with coordination between the dermatology and rheumatology departments&#44; nursing&#44; and hospital pharmacy</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Key Points and General Recommendations in the Prevention and Management of the Main Adverse Effects Caused by Apremilast &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p>"
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                      "titulo" => "Agencia Espa&#241;ola de Medicamentos y Productos Sanitarios &#40;AEMPS&#41;"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "Informe de Posicionamiento Terap&#233;utico de apremilast &#40;Otezla&#174;&#41;"
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                      "titulo" => "Agencia Espa&#241;ola de Medicamentos y Productos Sanitarios &#40;AEMPS&#41;"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Ficha t&#233;cnica Otezla&#174;"
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                      "Libro" => array:1 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Apremilast mechanism of action and application to psoriasis and psoriatic arthritis"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Schafer"
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                    0 => array:2 [
                      "doi" => "10.1016/j.bcp.2012.01.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Pharmacol"
                        "fecha" => "2012"
                        "volumen" => "83"
                        "paginaInicial" => "1583"
                        "paginaFinal" => "1590"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22257911"
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                  "contribucion" => array:1 [
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                      "titulo" => "Efficacy&#44; tolerability&#44; and pharmacodynamics of apremilast in recalcitrant plaque psoriasis&#58; a phase II open-label study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "R&#46;T&#46; Matheson"
                            2 => "A&#46; Menter"
                            3 => "C&#46;L&#46; Leonardi"
                            4 => "R&#46;M&#46; Day"
                            5 => "C&#46; Hu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Drugs Dermatol&#46;"
                        "fecha" => "2013"
                        "volumen" => "12"
                        "paginaInicial" => "888"
                        "paginaFinal" => "897"
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                          0 => array:2 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term experience with apremilast in patients with psoriatic arthritis&#58; 5-year results from a PALACE 1-3 pooled analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Kavanaugh"
                            1 => "D&#46;D&#46; Gladman"
                            2 => "C&#46;J&#46; Edwards"
                            3 => "G&#46; Schett"
                            4 => "B&#46; Guerette"
                            5 => "N&#46; Delev"
                          ]
                        ]
                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13075-019-1901-3"
                      "Revista" => array:5 [
                        "tituloSerie" => "Arthritis Res Ther&#46;"
                        "fecha" => "2019"
                        "volumen" => "21"
                        "paginaInicial" => "118"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31077258"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term safety and tolerability of apremilast in patients with psoriasis&#58; pooled safety analysis for &#8805;156 weeks from 2 phase 3&#44; randomized&#44; controlled trials &#40;ESTEEM 1 and 2&#41;"
                      "autores" => array:1 [
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Practical Dermatology
Multidisciplinary Management of the Adverse Effects of Apremilast
Manejo de los efectos adversos de apremilast desde un abordaje multidisciplinar
E. Daudén Telloa,
Autor para correspondencia
, J. Alonso Suárezb, E. Beltrán Catalánc, C. Blasco Maldonadod, M.C. Herrero Mansoe, A. Jiménez Moralesf, I. Marín-Jiménezg, M.D. Martín-Arranzh, A. García-Merinoi, J. Porta Etessamj, M.A. Rodríguez-Sagradok, J. Rosas Gómez de Salazarl, E. Trujillo Martínm, L. Salgado-Boqueten
a Servicio de Dermatología, Hospital Universitario La Princesa, Madrid, Spain
b Servicio de Dermatología, Hospital Universitario Virgen de la Victoria, Málaga, Spain
c Servicio de Reumatología, Hospital Parc Salut del Mar, Barcelona, Spain
d Unidad de Enfermería, Servicio de Dermatología, Hospital Universitario Puerta de Hierro, Madrid, Spain
e Unidad de Enfermería, Servicio de Reumatología, Hospital Universitario 12 de Octubre, Madrid, Spain
f Servicio de Farmacia, Hospital Universitario Virgen de las Nieves, Granada, Spain
g Unidad de EII-CEIMI-Servicio de Aparato Digestivo, Hospital Gregorio Marañón, Madrid, Spain
h Servicio de Aparato Digestivo, Hospital Universitario La Paz, Grupo de Inmunidad Innata, Instituto de Investigación IdiPaz, Madrid, Spain
i Servicio de Neurología, Hospital Universitario Puerta de Hierro, Madrid, Spain
j Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain
k Servicio de Farmacia, Hospital Universitario Ramón y Cajal, Madrid, Spain
l Sección de Reumatología, Hospital Marina Baixa, Villajoyosa, Alicante, Spain
m Servicio Reumatología, Hospital Universitario de Gran Canaria, Las Palmas de Gran Canaria, Spain
n Servicio de Dermatología, Complejo Hospitalario Universitario, Pontevedra, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0155" class="elsevierStylePara elsevierViewall">Since its approval by the European Commission in 2015&#44; apremilast has been used in the treatment of psoriasis and psoriatic arthritis in adult patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;5</span></a> The agent is an oral inhibitor of phosphodiesterase 4 &#40;PDE-4&#41; and has a good safety profile with a low incidence of adverse effects&#59; those that do occur are mainly of mild or moderate severity and largely involve the digestive tract&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> The incidence of these adverse effects is higher during the first 2 months of treatment and then decreases notably&#44; particularly from the second year of use onwards &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> They often resolve without need for medical intervention or dose adjustment&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Although the rate of treatment discontinuations due to adverse effects was less than 2&#37; during clinical development&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> a higher rate of apremilast discontinuations has been reported in clinical practice &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">In order to assess the strategies available for management of adverse effects that most often lead to treatment discontinuation in patients with psoriasis and&#47;or psoriatic arthritis &#40;diarrhea&#44; nauseas&#44; and headache&#41;&#44; a multidisciplinary committee of experts in rheumatology&#44; dermatology&#44; neurology&#44; gastroenterology&#44; hospital pharmacy&#44; and nursing&#44; belonging to 14 Spanish hospitals&#44; conducted a broad review of the literature&#44; with special focus on the general pathophysiology of each adverse effect from the point of view of their particular specialty&#46; After considering this information and personal experience&#44; a series of consensus recommendations were made&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Headache</span><p id="par0165" class="elsevierStylePara elsevierViewall">Drug-induced headaches are a neurological process triggered by activation of pain-modulating structures in the central or peripheral nervous system&#46; A migraine attack can be triggered through action on different structures involved in its pathophysiology or by altering the antinociceptive structures that are responsible for migraine resolution&#46; In the framework of pathophysiology of migraines&#44; in recent years&#44; the importance of neuropeptides that participate in genesis of pain and other typical symptoms of migraine has been increasingly recognized&#46; Release of neuropeptides leads to nerve fiber sensitization &#40;neuronal hyperexcitability&#41;&#44; thereby enhancing central and peripheral pain and inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Calcitonin gene-related peptide &#40;CGRP&#41;&#44; pituitary adenylate cyclase-activating peptide &#40;PACAP&#41;&#44; and their respective receptors are one of the main targets for new migraine therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Although the mechanism that triggers headache after administration of PDE-4 inhibitors has not been elucidated&#44; it could be related to release of peptides that induce symptoms similar to migraine&#46; The participation of PACAP and other neuropeptides could be responsible for the appearance of these symptoms&#44; such that we might be facing 2 situations&#58; 1&#41; patients with migraine who see their pain exacerbated&#44; whether in intensity or frequency&#44; and 2&#41; patients who have had not suffered from headache and who start with a throbbing headache with sensitization &#40;pathophysiology similar to migraine&#41; or a headache with a different profile&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients With History of Headache Before Treatment With Apremilast</span><p id="par0175" class="elsevierStylePara elsevierViewall">For patients with a history of migraine&#44; there is the option of administering preventive treatment 2 weeks before starting apremilast therapy&#44; as later administration may lead to a delay in the resolution of symptoms&#46; Melatonin&#44; at a dose of 3&#8239;mg&#47;mg&#44; could be a good option for preventive treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> with triptanes as an option in the event of a migraine attack &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Sumatriptan&#44; at a dose of 25&#8211;100&#8239;mg&#47;day&#44; is indicated for acute treatment of intermittent migraine&#44; with or without aura&#46; If the patient responds after the first dose&#44; and symptoms recur&#44; a second dose could be administered in the following 24&#8239;h if more than 2&#8239;h have elapsed since the first dose &#40;maximum 300&#8239;mg&#47;day&#41;&#46; Adverse effects that have been reported frequently for sumatriptan include general disorders &#40;weakness&#44; fatigue&#44; pressure&#41; and musculoskeletal disorders &#40;heaviness&#44; myalgia&#41;&#44; which are generally transient and of mild or moderate intensity&#46; Other reactions include dyspnea&#44; increased blood pressure&#44; dizziness&#44; somnolence&#44; and sensory abnormalities&#46; In the event of lack of response to sumatriptan&#44; treatment with paracetamol or nonsteroidal anti-inflammatory drugs &#40;NSAIDs&#41; is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">Alternatively&#44; other preventive therapies include amitriptyline or beta-blockers&#44; depending on the profile of the patient&#46; The initial recommended dose of amitriptyline is 10&#8211;25&#8239;mg&#44; before going to bed&#44; with an increase of 10&#8211;25&#8239;mg every 3&#8211;7 days&#44; depending on the tolerance of the patient &#40;maximum 25&#8211;75&#8239;mg&#47;day&#41;&#46; The analgesic effect is usually felt after 2&#8211;4 weeks of treatment&#44; and the most frequent adverse effects include&#58; aggression&#44; somnolence&#44; dizziness&#44; headache&#44; blurry vision&#44; palpitations&#44; tachycardia&#44; constipation&#44; nausea&#44; dry mouth&#44; weight gain&#44; nasal congestion&#44; hyperhidrosis&#44; and orthostatic hypotension&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Of the beta-blockers&#44; propranolol is indicated for prophylactic treatment of migraine with an initial dose of 40&#8239;mg 2 or 3 times a day&#44; with increments by the same amount over weekly intervals depending on the response of the patient up to 80&#8211;160&#8239;mg&#47;day &#40;maximum 240&#8239;mg&#47;day&#41;&#46; It should be remembered that administration of propranolol may cause fatigue&#44; bradycardia&#44; cold hands and feet&#44; Raynaud phenomenon&#44; and sleep disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> It should also be remembered that beta-blockers&#44; and propranolol in particular&#44; belong to the group of drugs able to induce or exacerbate psoriasis&#46; A careful assessment of the benefit&#47;risk profile is therefore important prior to recommending its use&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Patients With Headache That Presents After Starting Treatment With Apremilast</span><p id="par0185" class="elsevierStylePara elsevierViewall">In patients who present with headache after administration of apremilast&#44; 3 differential characteristics of the type of headache should be considered&#58; 1&#41; the throbbing component&#59; 2&#41; whether it worsens with activity and&#47;or head movement&#59; and 3&#41; if photophobia is present &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The presence of these 3 components corresponds to a profile of meningeal inflammation denoted migraine type&#46; Therapeutic intervention is only necessary when the headaches have an impact on the quality of life of the patient&#46; In this case&#44; treatment for this type of headache is based on administration of NSAIDs&#44; such as for example naproxen and ibuprofen&#44; or triptanes &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; As a general regimen&#44; daily doses of naproxen range from 550&#8239;mg to 1&#46;1&#8239;g&#44; with a recommended starting dose of 550&#8239;mg followed by 275&#8239;mg every 6&#8211;8&#8239;h&#44; depending on the intensity of the headache&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The daily recommended dose of ibuprofen is 1&#46;2&#8211;1&#46;8&#8239;g&#44; administered over several doses and without exceeding a dose of 2&#46;4&#8239;mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In contrast&#44; if the headache is of the tension type&#44; treatment with paracetamol or metamizole is recommended&#44; with the additional use of an NSAID also an option&#46; A regimen of 500&#8239;mg of paracetamol every 4&#8211;6&#8239;h or 1&#8239;g every 8&#8239;h is recommended&#44; without exceeding the maximum dose of 3&#8239;g&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Metamizole can be administered at a dose of 575&#8239;mg &#40;a capsule&#41; 3 or 4 times a day for a week&#44; without exceding the maximum dose of 6 capsules&#47;day&#46; Reactions of hypotension can present during or after treatment with metaizol&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diarrhea</span><p id="par0190" class="elsevierStylePara elsevierViewall">Diarrhea caused by PDE-4 inhibitors is considered of a secretory nature&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The increase in intracellular cAMP caused by PDE-4 inhibition can trigger intestinal secretion through activation of chlorine channels in the apical membrane of the enterocytes and inhibition of NaCl absorption&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;19</span></a> Different isoforms of PDE-4 interact with the cystic fibrosis transmembrane conductance regulator &#40;CFTR&#41;&#44; a chlorine channel implicated in secretion and homeostasis&#44; whose hyperactivation may give rise to secretory diarrhea&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Through protein kinase A &#40;PKA&#41;&#44; cAMP also promotes intestinal secretion by activation of different membrane proteins in the enterocytes&#44; such as K<span class="elsevierStyleSup">&#43;</span> and anion channels and NaK<span class="elsevierStyleInf">2</span>Cl transporters&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In addition&#44; it has been suggested that early resolution of symptoms associated with diarrhea caused by apremilast &#40;in approximately 2 weeks&#41; could be due to upregulation of other PDEs in the intestine&#44; as a compensatory mechanism for PDE-4 inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">As described for headache&#44; the best strategy for appropriate management of gastrointestinal adverse effects&#44; when considered necessary&#44; is to administer a treatment that is thought to act effectively on the underlying pathophysiology&#46; Preventive measures such as administration of apremilast during meals&#44; avoiding excessive liquid intake or intake of caffeine and sweeteners could reduce or delay the onset of symptoms of secretory diarrhea caused by apremilast&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Although not fully accepted&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> it is possible that administration of probiotics could reduce the symptoms associated with gastrointestinal intolerance&#44; thus permitting better therapeutic compliance and a lower discontinuation rate&#46; On the other hand&#44; fiber supplements and administration of bismuth subsalicylate may be used as a complementary therapy to reduce water loss and the number of depositions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In any case&#44; it is recommended to follow a simple treatment regimen that is not accompanied by major changes in the patient&#8217;s lifestyle&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Apremilast-induced diarrhea is usually self-limiting and resolves in the first few weeks of treatment&#46; If pharmacological intervention is deemed necessary&#44; secretory diarrhea could be treated effectively with racecadotril&#44; an antisecretory agent that can be used for the treatment of apremilast-induced diarrhea &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Racecadotril acts by inhibiting intestinal encephalinase&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> thus reducing water and electrolyte secretion to the intestinal lumen&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Administration of 100&#8239;mg every 8&#8239;h&#44; preferably before meals&#44; has been shown to shorten the duration of diarrhea symptoms&#44; reduce the number of depositions&#44; and reduce the need for rehydration&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> This regimen is recommended to continue for 7 days&#44; until attaining 2 depositions&#47;day&#46; Adverse skin reactions&#44; generally moderate&#44; have been reported&#44; along with headache and cases of hypersensitivity&#47;angioneurotic edema in patients in treatment with racecadotril&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Other pharmacological options for the treatment of diarrhea caused by apremilast include loperamide and codeine&#46; Loperamide is indicated for treatment of acute diarrhea with an initial dose of 4&#8239;mg &#40;2 tablets&#41;&#44; continuing with 1 tablet after each deposition&#44; for a maximum of 2 days and 4 tablets&#47;day&#46; Gastrointestinal disorders &#40;nausea and dysgeusia&#41; have often been reported after treatment with loperamide&#46; If clinical improvement is not observed in 48&#8239;h&#44; or if symptoms of constipation&#44; ileus&#44; or abdominal distension appear&#44; administration of loperamide should be discontinued&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In the case of treatment with codeine&#44; the recommended regimen is 1 tablet &#40;21&#46;4&#8239;mg&#41; every 6&#8239;h&#59; this can be increased to 2 tablets per administration&#44; for a maximum duration of 2 days&#44; administering 6 tablets&#47;day&#46; Administration of codeine can cause somnolence and alcohol intake should be avoided during treatment&#44; as this can enhance the depressor effect on the CNS&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Nausea</span><p id="par0205" class="elsevierStylePara elsevierViewall">Nausea induced by PDE-4 inhibitors appears to be triggered by central and peripheral mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;29</span></a> This adverse effect has been associated with lack of selectivity of PDE-4 inhibitors for the different isoforms &#40;A&#44; B&#44; C&#44; D&#41; expressed in different cell types&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> Specifically&#44; the PDE-4 D isoform is expressed in neurons of the area postrema&#44; where the chemoreceptor trigger zone that links with the vomit center is located&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The increase in intracellular levels of cAMP in neurons of the area postrema ultimately triggers the emetic response&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> While apremilast has been reported to be highly specific for PDE-4&#44; it has a similar potency for each of the different isoforms of this enzyme&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;31&#44;32</span></a> The lack of selectivity for the PED-4 isoform could explain the improved therapeutic index of apremilast in in vivo models compared with other PDE-4 inhibitors for gastrointestinal adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Among these nonpharmacological interventions&#44; frequent smaller meals as well as limited liquid intake during meals may help reduce the sensation of nausea&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> As with the preventive measures for diarrhea&#44; a simple and personalized approach is recommended according to the patient&#8217;s characteristics&#44; without limiting his or her quality of life&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Ondansetron is a potent and highly selective serotonergic 5HT<span class="elsevierStyleInf">3</span> antagonist that blocks the vomiting reflex at both the central and peripheral level&#46; It is therefore indicated for controlling nausea and vomiting following surgery or induced by radiotherapy or cytotoxic chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Given its high efficacy as an antiemetic and its good tolerability&#44; ondansetron could be considered a good pharmacological option for treatment of nausea that persists during treatment with apremilast &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Ondansetron can be administered orally or intravenously&#44; with the oral regimen being 8&#8239;mg between 1 or 2&#8239;h prior to emetogenic treatment&#44; followed by 8&#8239;mg every 12&#8239;h for up to a maximum of 5 days&#46; The most frequently reported adverse effects are headache&#44; burning sensation &#40;hot flushes&#41;&#44; and constipation&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> It should be remembered that ondansetron is not currently reimbursed under the Spanish National Health System&#44; and so its use would require an off-label request&#46; Alternatively&#44; metoclopramide could be used&#46; This is a neuroleptic agent with antiemetic properties used for prevention and symptomatic treatment of nausea and vomiting&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> A single dose of 10&#8239;mg of metoclopramide is recommended&#46; This dose can be repeated up to 3 times a day&#44; with at least 6&#8239;h between dosing &#40;even in the case of vomiting or dose rejection&#41; up to maximum duration of 5 days&#46; During treatment with metoclopramide&#44; particularly when used at high doses&#44; adverse effects such as diarrhea&#44; asthenia&#44; somnolence&#44; extrapyramidal disorders&#44; parkinsonism&#44; akathisia&#44; depression&#44; and hypotension may appear&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0220" class="elsevierStylePara elsevierViewall">The possibility should also be considered that nausea is not a direct result of apremilast treatment but rather a side effect of the neurological adverse effects described above&#46; It is therefore recommended to evaluate each case individually&#44; and tailor management of the adverse effect that has triggered the symptoms in the first place&#46; Metoclopramide is also indicated for the treatment of nausea and vomiting induced by acute migraine&#44; and can be administered in combination with oral analgesics to improve absorption of these analgesics&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">General Recommendations</span><p id="par0225" class="elsevierStylePara elsevierViewall">Taking into consideration the above&#44; a series of general recommendations are derived to facilitate the prevention and management of possible adverse effects caused by apremilast in clinical practice &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#44; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0230" class="elsevierStylePara elsevierViewall">Adverse effects caused by apremilast should be managed in a multidisciplinary setting&#46; Optimization of their management would no doubt be of clinical benefit to patients affected by these adverse effects&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of Interest</span><p id="par0235" class="elsevierStylePara elsevierViewall">Esteban Daud&#233;n&#58; advisory board member&#44; consultant&#44; grant recipient&#44; research support&#44; participation in clinical trials&#44; speaker fees with the following pharmaceutical companies&#58; Abbott&#47;AbbVie&#44; Almirall&#44; Amgen&#44; Biogen&#44; Celgene&#44; Janssen-Cilag&#44; Leo Pharma&#44; Lilly&#44; MSD&#44; Novartis&#44; and Pfizer&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Jorge Alonso Su&#225;rez&#58; advisory board member&#44; consultant&#44; grant recipient&#44; research support&#44; participation in clinical trials&#44; speaker fees with the following pharmaceutical companies&#58; AbbVie&#44; Almirall&#44; Janssen-Cilag&#44; Leo Pharma&#44; Novartis&#44; Pfizer&#44; Celgene&#44; Lilly&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">M&#46; Carmen Herrero Manso&#58; consultancy&#44; courses&#44; book chapters&#44; or congress attendance with UCB Pharma&#44; Celgene&#44; MSD&#44; Pfizer&#44; Mylan&#44; BMS&#44; AbbVie&#44; Janssen&#44; Sandoz&#44; Gedeon Richter&#44; Novartis&#44; Lilly&#44; Gebro&#44; Nordic&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Ignacio Mar&#237;n-Jim&#233;nez&#58; consultancy&#44; support for investigations or congress attendance with&#58; AbbVie&#44; Amgen&#44; Celgene&#44; Dr&#46; Falk Pharma&#44; Faes Farma&#44; Ferring&#44; Fresenius&#44; Janssen&#44; MSD&#44; Pfizer&#44; Sandoz&#44; Takeda&#44; and UCB-Pharma&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">M&#46; Dolores Mart&#237;n-Arranz&#58; Advisory Board member and support for investigation with the following pharmaceutical companies&#58; MSD&#44; AbbVie&#44; Hospira&#44; Pfizer&#44; Takeda&#44; Janssen&#44; Shire Pharmaceuticals&#44; Tillotts Pharma&#44; Faes Farma&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Miguel A&#46; Rodr&#237;guez-Sagrado&#58; renumerated activities for AbbVie&#44; Biogen&#44; Celgene&#44; Gilead&#44; Intercept&#44; Janssen&#44; Merck-Serono&#44; MSD&#44; Novartis&#44; Roche&#44; Sandoz&#44; Tesaro&#44; and ViiV&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Jos&#233; Rosas G&#243;mez de Salazar&#58; Advisory Board member&#58; AbbVie&#44; Celgene&#44; Grifols&#44; Janssen&#44; Lilly&#44; Pfizer&#46; Speakers fees&#58; Amgen&#44; Grifols&#44; Janssen&#44; Lilly&#44; MSD&#44; Novartis&#44; Pfizer&#44; Stada</p><p id="par0270" class="elsevierStylePara elsevierViewall">Laura Salgado-Boquete&#58; advisory board member&#44; consultant&#44; grant recipient&#44; research support&#44; participation in clinical trials&#44; speaker fees from the following pharmaceutical companies&#58; AbbVie&#44; Almirall&#44; Janssen-Cilag&#44; Leo Pharma&#44; Novartis&#44; Pfizer&#44; MSD-Schering-Plough&#44; Celgene&#44; Lilly&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">The remaining authors declare that they have no conflicts of interest&#46;</p></span></span>"
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              "identificador" => "sec0015"
              "titulo" => "Patients With History of Headache Before Treatment With Apremilast"
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              "titulo" => "Patients With Headache That Presents After Starting Treatment With Apremilast"
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          "titulo" => "Diarrhea"
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            2 => "Headache"
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            1 => "Psoriasis"
            2 => "Cefalea"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">We present a series of general and specific recommendations based on pathophysiologic considerations for managing the most common adverse effects of apremilast that lead to treatment discontinuation&#58; diarrhea&#44; nausea&#44; and headache&#46; The recommendations are based on a review of the literature and the experience of a multidisciplinary team of 14 experts including dermatologists&#44; rheumatologists&#44; neurologists&#44; gastroenterologists&#44; pharmacists&#44; and nurses&#46; We propose a series of simple algorithms that include clinical actions and suggestions for pharmacologic treatment&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">The adverse effects of apremilast can be managed from a multidisciplinary approach&#46; The purpose of optimizing management is to bring clinical benefits to patients&#46;</p></span>"
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        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">En el presente art&#237;culo&#44; en base a una revisi&#243;n de la literatura y su experiencia personal&#44; un equipo multidisciplinar de 14 profesionales sanitarios &#40;incluyendo dermat&#243;logos&#44; reumat&#243;logos&#44; neur&#243;logos&#44; gastroenter&#243;logos&#44; farmac&#233;uticos y enfermeras&#41; ha elaborado una serie de recomendaciones generales y espec&#237;ficas &#40;basadas en la fisiopatolog&#237;a&#41; para el manejo de los efectos adversos secundarios a apremilast que con mayor frecuencia conducen a la suspensi&#243;n del tratamiento &#40;diarrea&#44; n&#225;useas y cefalea&#41;&#46; Se aportan algoritmos sencillos de manejo que incluyen aspectos cl&#237;nicos de evaluaci&#243;n y sugerencias de tratamiento farmacol&#243;gico&#46;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Los efectos adversos de apremilast pueden ser abordados desde un punto de vista multidisciplinar y la optimizaci&#243;n en su manejo pretende proporcionar un beneficio cl&#237;nico a los pacientes que los sufren&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Daud&#233;n Tello E&#44; Alonso Su&#225;rez J&#44; Beltr&#225;n Catal&#225;n E&#44; Blasco Maldonado C&#44; Herrero Manso MC&#44; Jim&#233;nez Morales A&#44; et al&#46; Manejo de los efectos adversos de apremilast desde un abordaje multidisciplinar&#46; Actas Dermosifiliogr&#46; 2021&#59;112&#58;134&#8211;141&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; NE&#44; not evaluated&#59; PsA&#44; psoriatic arthritis&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Adapted from Crowley et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and Kavanaugh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p>"
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                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 1&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 2&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 3&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 4&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year 5&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diarrhea</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nausea</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;4&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tension headache</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Psoriasis&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PsA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2517094.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Frequency of Adverse Drug Reactions Reported During Long-term Follow-up of Apremilast Treatment&#46;</p>"
        ]
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      5 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0030"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; CP&#44; clinical practice&#59; CT&#44; combined analysis of clinical trials&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Adapted from Ighani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Frequency of adverse effect&#44; &#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CT&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;1&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CP&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;4&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;9&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 " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment discontinuation&#44; &#37;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CT&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;6&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CP&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2517092.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Frequency of Adverse Drug Reactions and Treatment Discontinuation of Apremilast for the Treatment of Psoriasis in Clinical Trials and Clinical Practice&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0035"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prior Considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Preventive Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pharmacological Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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">Headache</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Only in case of headache prior to treatment</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Migraine type</span>&#58;&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 " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Patients with history of headache before starting apremilast treatment</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">Melatonin&#58; 3&#8239;mg&#47;day</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">Amitriptyline&#58; 10&#8722;25&#8239;mg&#47;day with increase every 3&#8722;7&#8239;d &#40;maximum 25&#8722;75&#8239;mg&#47;day&#41;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Beta-blockers<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#58; propranolol 40&#8239;mg 2&#8211;3&#8239;times&#47;day with weekly increase to 80&#8722;160&#8239;mg&#47;day &#40;maximum 240&#8239;mg&#47;day&#41;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0020" class="elsevierStylePara elsevierViewall">Triptanes &#40;in case of migraine attack&#41;&#58; sumatriptan 25&#8722;100&#8239;mg&#47;day</p></li></ul></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">NSAID&#58; naproxen 550&#8239;mg&#8239;&#43;&#8239;275&#8239;mg every 6&#8722;8&#8239;h&#59; ibuprofen 1&#46;2&#8722;1&#46;8&#8239;g&#47;day in several doses</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Triptanes&#58; sumatriptan 25&#8722;100&#8239;mg&#47;day</p></li></ul>&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tension type</span>&#58;&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Paracetamol&#58; 500&#8239;mg every 4&#8722;6&#8239;h or 1&#8239;g every 8&#8239;h</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Metamizole&#58; 575&#8239;mg 3&#8722;4&#8239;times&#47;day &#40;maximum 7&#8239;days&#41;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">NSAID&#58; naproxen 550&#8239;mg &#43;&#8239;275&#8239;mg every 6&#8722;8&#8239;h&#59; ibuprofen 1&#46;2&#8722;1&#46;8&#8239;g&#47;day in several doses</p></li></ul>&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="elsevierStyleItalic">Diarrhea</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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Frequent smaller meals</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Limit liquid intake during meals</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Consider avoiding dairy products&#44; caffeine&#44; and artificial sweeteners</p></li></ul>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Racecadotril&#58; 100&#8239;mg every 4&#8722;6&#8239;h for 7&#8239;days</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Loperamide&#58; 2 tablets &#40;4&#8239;mg&#41; and then 1 after every deposition &#40;maximum 4&#8239;tablets&#47;day for 2&#8239;days&#41;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Codeine&#58; 1&#8722;2 tablets &#40;21&#46;4&#8239;mg&#47;tablet&#41; every 6&#8239;h &#40;maximum 6 tablets&#47;day for 3&#8239;days&#41;</p></li></ul>&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="elsevierStyleItalic">Nausea</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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Frequent smaller meals</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Limit liquid intake during meals</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Avoid activity after eating</p></li></ul></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Ondansetron&#58; 8&#8239;mg before first apremilast treatment and then every 12&#8239;h</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Metoclopramide&#58; 10&#8239;mg&#44; 3&#8239;times&#47;day</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">For a maximum of 5 days</p></li></ul></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>Relationship with headache caused by apremilast treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2517093.png"
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          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Beta-blockers can induce or exacerbate psoriasis&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Management of Headache&#44; Diarrhea&#44; and Nausea Caused by Apremilast Treatment&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0040"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><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"><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">The onset of adverse effects caused by apremilast therapy usually occurs in the first 2&#8722;4&#8239;weeks of treatment&#44; and they are usually self-limiting and resolve spontaneously in the initial phases of treatment</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">If pharmacological treatment is required and if the diarrhea&#44; nausea&#44; or headache persist despite treatment&#44; negatively impacting the patient&#8217;s quality of life&#44; the options of referring him or her to the gastroenterology or neurology department could be considered</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">The decision to refer the patient to another department and&#47;or discontinue treatment with apremilast should be taken on an individual basis&#44; taking into account the expectations of apremilast treatment compared with other available drugs&#44; as well as the delay at each center in obtaining multidisciplinary care or care in another department</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">As an alternative to the treatments considered above&#44; lengthening the initial apremilast escalation regimen by 1&#8722;2&#8239;weeks and&#47;or using lower doses &#40;30&#8239;mg&#47;day&#41; could help reduce adverse effects that develop in early phases of treatment</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">With the aim of avoiding early discontinuation of treatment by the patient&#44; it is recommended to provide him or her with sufficient information on the possible adverse effects &#40;type&#44; estimated duration&#44; and treatment&#41; before starting therapy with apremilast</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Performing a follow-up visit at 1 month after starting therapy helps minimize and promptly resolve adverse effects&#44; improving the patient&#8217;s therapeutic compliance</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8226;</span><p id="par0140" class="elsevierStylePara elsevierViewall">An appropriate communication system &#40;telephone contact&#44; nursing visit&#44; support service&#44; etc&#46;&#41; will help the patient have ready access to health care professionals to resolve doubts about management of possible adverse effects</p></li></ul>&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"><ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">It is recommended that the patient is sufficiently well informed and is provided with the prophylactic and therapeutic options available before discontinuing treatment</p></li></ul>&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
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