Practical Management of Immunosuppressants in Dermatology

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A retrospective observational study was carried out based on a review of medical records (anonymized) of patients diagnosed with atopic dermatitis. Patients were followed for 1 year. AD indicates atopic dermatitis." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Sicras-Mainar, R. Navarro-Artieda, J.M. Carrascosa Carrillo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Sicras-Mainar" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Navarro-Artieda" ] 2 => array:2 [ "nombre" => "J.M." 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A, Panoramic view showing a spiradenoma in the dermis and a spiradenocarcinoma nodule in the subcutaneous tissue. B, The nodule is formed by a sheet of neoplastic cells. C, Note the pleomorphic nuclei and frequent mitotic figures in the neoplastic cells. D. High-magnification view of neoplastic cells, several of which are in mitosis. (Hematoxylin-eosin, original magnification ×10 [A], ×40 [B], ×200 [C], ×400 [D])." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Bernárdez, L. Requena" "autores" => array:2 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Bernárdez" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Requena" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731017302077" "doi" => "10.1016/j.ad.2017.04.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731017302077?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219017303591?idApp=UINPBA000044" "url" => "/15782190/0000010900000001/v1_201801020547/S1578219017303591/v1_201801020547/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Practical Dermatology" "titulo" => "Practical Management of Immunosuppressants in Dermatology" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "24" "paginaFinal" => "34" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "V.M. Leis-Dosil, I. Prats-Caelles" "autores" => array:2 [ 0 => array:4 [ "nombre" => "V.M." "apellidos" => "Leis-Dosil" "email" => array:1 [ 0 => "vmanuel.leis@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Prats-Caelles" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Sección de Dermatología, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, España" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Manejo práctico de inmunosupresores en dermatología" ] ] "textoCompleto" => "IntroductionDermatologic autoimmune or inflammatory diseases are usually managed with immunosuppressants. Care must be taken to find a point of balance that attenuates the abnormal inflammatory response while causing the least possible immunosuppression.The prescriber must be aware of each immunosuppressant's unique time to onset of action, level of acute toxicity, and dosage regimens. An intense, rapid response is sometimes warranted, but a goal in other circumstances might be a treatment that can be followed over the long term.This review deals with classic immunosuppressants. Neither glucocorticoids nor biologics will be discussed.Pretreatment Tests and VaccinationsBefore suppressing a patient's immune response, information is required for ruling out contraindications, tailoring the dosage, and planning measures to reduce inherent risk.Certain laboratory tests are needed for prescribing any of these drugs, but particular immunosuppressants also have specific requirements<a class="elsevierStyleCrossRef" href="#bib0390">1</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Because vaccination coverage should be on record for all patients, serology is included in the test battery.<a class="elsevierStyleCrossRefs" href="#bib0395">2–5</a> If the patient's clinical condition permits, required vaccinations or booster doses should be scheduled at least 2 weeks before immunosuppressant therapy starts. If vaccination is not feasible beforehand, it should not be undertaken until at least 3 months after treatment stops given that live virus vaccines carry the risk of infection, and immunization may not be achieved if inactivated viruses are used.Vaccination against varicella should be tailored to the individual. If a pediatric vaccination schedule must be followed, immunosuppressants should be interrupted 2 weeks before vaccination and not restarted until 2 weeks afterwards.<a class="elsevierStyleCrossRef" href="#bib0415">6</a>Two types of pneumococcal vaccines are available: the 23-valent polysaccharide (PPSV23) and 13-valent conjugate (PCV13) versions. Spanish health authorities stipulate a sequential vaccination schedule for patients on immunosuppressants.<a class="elsevierStyleCrossRef" href="#bib0420">7</a> The schedule starts with a dose of PCV13 before treatment and is followed by a dose of PPSV23 at least 8 weeks later. If the patient is already under treatment, these criteria should be applied when the first consultation takes place. A booster dose of PPSV23 should be given at 5 years.Patients on immunosuppressants should receive the same influenza vaccination produced for the general population every year.<a class="elsevierStyleCrossRef" href="#bib0425">8</a>Certain factors affect the choice of one immunosuppressant drug (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) over another:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•whether or not the patient has a medical history that includes a contraindication for a particular immunosuppressant or new testing reveals such a contraindication,</li><li class="elsevierStyleListItem" id="lsti0010">•whether or not the drug's summary of product characteristics includes the patient's disease,<a class="elsevierStyleCrossRefs" href="#bib0430">9–13</a></li><li class="elsevierStyleListItem" id="lsti0015">•whether or not an intense, rapid response is required,</li><li class="elsevierStyleListItem" id="lsti0020">•or alternatively, whether the prescriber seeks a maintenance of effect over a long course of treatment.</li></ul><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Practical Aspects of Immunosuppressant TherapyOnce an immunosuppressant is selected, it must be fully understood if we are to achieve the best results for our patient. For practical purposes we will analyze the main aspects relevant to managing the immunosuppressants most often prescribed by dermatologists (<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3–7</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="tbl0035"></elsevierMultimedia>MethotrexateMethotrexate, an antimetabolite analog of folic acid, inhibits dihydrofolate reductase. It is unquestionably one of the most often prescribed immunosuppressants in dermatology.<a class="elsevierStyleCrossRef" href="#bib0455">14</a>Although psoriasis is the only indication listed in the product summary,<a class="elsevierStyleCrossRefs" href="#bib0450">13,15,16</a> many studies have supported this drug's use in other conditions.<a class="elsevierStyleCrossRef" href="#bib0470">17</a> Some examples are autoimmune bullous diseases<a class="elsevierStyleCrossRef" href="#bib0475">18</a>; severe adult atopic dermatitis<a class="elsevierStyleCrossRef" href="#bib0480">19</a>; alopecia areata<a class="elsevierStyleCrossRef" href="#bib0485">20</a>; chronic urticaria<a class="elsevierStyleCrossRef" href="#bib0490">21</a>; cutaneous lupus erythematosus<a class="elsevierStyleCrossRefs" href="#bib0495">22,23</a>; sarcoidosis, scleroderma, lymphomatoid papulosis and other lymphoproliferative disorders<a class="elsevierStyleCrossRefs" href="#bib0470">17,24</a>; and keratoacanthomas.<a class="elsevierStyleCrossRef" href="#bib0510">25</a>Methotrexate is available in tablets of 2.5mg and syringes prefilled with doses ranging from 7.5 to 30mg (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Oral administration is much more economical than parenteral injection and the bioequivalence is similar, at least up to a weekly dose of 17.5mg.<a class="elsevierStyleCrossRefs" href="#bib0455">14,16</a> However, gastrointestinal symptoms are common with oral intake, and injections are therefore recommended when the dose exceeds 15mg to prevent digestive intolerance. Parenteral administration is also advisable when the patient is at risk of confusing doses or adherence is poor.<a class="elsevierStyleCrossRef" href="#bib0515">26</a>The patient must be told that the drug is taken or injected once a week, not daily, if serious side effects are to be avoided.<a class="elsevierStyleCrossRefs" href="#bib0470">17,26</a> It is good practice to establish a particular time each week that takes into consideration that the dose will be followed by days of discomfort and that samples for laboratory tests must be collected the day before dosing, as long as possible before the drug is actually taken. The entire oral dose can be ingested at once or in 2 or 3 fractions separated by 12hours.<a class="elsevierStyleCrossRef" href="#bib0460">15</a>A test dose is not currently considered necessary.<a class="elsevierStyleCrossRef" href="#bib0520">27</a> A starting dosage of 7.5 to 15mg/wk should be given and gradually increased until the response is satisfactory. Increases of 2.5 to 5mg can be tried every 4 to 6 weeks.<a class="elsevierStyleCrossRefs" href="#bib0470">17,19</a> Responders usually improve at 4weeks, but we have waited up to 12weeks before deciding that treatment has failed. A regimen of 15mg/wk is usually effective. The approach should be reviewed if 25mg/wk is exceeded.<a class="elsevierStyleCrossRef" href="#bib0515">26</a>The strategy to follow is similar in psoriasis and other diseases. In autoimmune bullous diseases, for example, certain patients are nonresponders (13% in pemphigus vulgaris, 4% in bullous pemphigoid), and no data on predictors of failure are available. On the other hand, mortality due to serious infection is considerable (3.7% in pemphigus vulgaris, 2.5% in bullous pemphigoid). Nonetheless methotrexate therapy remains a good corticosteroid-sparing strategy.<a class="elsevierStyleCrossRef" href="#bib0475">18</a>Methotrexate should be accompanied by folic or folinic acid supplementation, which significantly reduces adverse effects on the liver and nonsignificantly improves effects on mucosal, gastrointestinal and blood tissues but does not prevent the development of pulmonary fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0515">26,28</a> Some studies consider supplementation to be contraindicated in the interest of efficacy, but a reduction in methotrexate's effect with folic acid is fairly unlikely<a class="elsevierStyleCrossRef" href="#bib0525">28</a> because the 2 drugs promote the anti-inflammatory action of adenosine through different mechanisms.<a class="elsevierStyleCrossRef" href="#bib0465">16</a> Folic acid and folinic acid do not appear to differ in effectiveness, and the former is less costly. Dosage regimens are debated. They vary from 5 to 30mg/wk unless other conditions requiring folic or folinic acid supplementation are present, in which case 5mg/week taken 24 to 48hours after the methotrexate dose should be sufficient.<a class="elsevierStyleCrossRef" href="#bib0515">26</a>One of the main adverse effects of methotrexate is liver fibrosis. One systematic review found that the risk for fibrosis increased 22% in patients with methotrexate-treated psoriasis; however, risk was not significantly related to duration of therapy or cumulative dose.<a class="elsevierStyleCrossRef" href="#bib0530">29</a> The authors therefore concluded that fibrosis develops only in a certain subgroup of patients whose characteristics could not be determined due to the low quality of evidence provided by the studies reviewed. It is likely that comorbid conditions such as obesity or alcohol intake exacerbate risk in some. A noninvasive means for detecting fibrosis without resorting to liver biopsy is required. The most widely studied approaches are the measurement of biomarkers (eg, procollagen type III N-terminal peptide<a class="elsevierStyleCrossRef" href="#bib0535">30</a>) and the use of imaging techniques such as elastography (eg, FibroScan). One meta-analysis showed that these 2 techniques applied individually have low discriminatory power in screening.<a class="elsevierStyleCrossRef" href="#bib0540">31</a> However, combining various biomarkers (eg, in the enhanced liver fibrosis panel) or biomarkers and imaging may be more useful.CiclosporinCiclosporin is a calcineurin inhibitor that acts on T cells.The summary of product characteristics for this drug lists psoriasis and atopic dermatitis as the dermatologic indications. However, ciclosporin has been used to effectively treat Stevens–Johnson syndrome,<a class="elsevierStyleCrossRef" href="#bib0545">32</a> lichen planus and lichen planopilaris,<a class="elsevierStyleCrossRef" href="#bib0550">33</a> pyoderma gangrenosum, chronic urticaria, autoimmune blistering diseases, suppurative hidradenitis, and more.<a class="elsevierStyleCrossRefs" href="#bib0555">34,35</a>The great advantage of ciclosporin is its rapid onset of action. Good control of disease can be achieved in a few months with a short treatment cycle.Dose regimens range from 2.5 to 5mg/kg/d<a class="elsevierStyleCrossRef" href="#bib0565">36</a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). Although ciclosporin is lipophilic, it is important to remember that distribution is mainly through lean tissues. Therefore, when the real weight of obese patients is used to calculate the dosage, the concentration of the circulating drug will be elevated and there is risk of toxicity. Consequently, the dose should be calculated based on the patient's ideal weight.<a class="elsevierStyleCrossRef" href="#bib0570">37</a>The daily dose is usually divided into 2 fractions. Taking ciclosporin before food intake has been shown to facilitate absorption, allow for lower doses and favor more even, predictable pharmacokinetics. Ciclosporin should therefore be taken before breakfast and before the evening meal.<a class="elsevierStyleCrossRef" href="#bib0575">38</a>It is generally not recommended to prolong treatment beyond 1 year because long treatment cycles carry greater risk of toxicity. However, strategies that allow treatment to be maintained as long as possible have been explored. The 2 usual approaches, particularly in psoriasis, involve rotations and combinations that allow for lower daily doses. Weekend pulse therapy is another possibility once a conventional regimen has acheived control of disease. This regimen consists of prescribing a maintenance dose of up to 5mg/kg/d for 2 consecutive days per week and resting for the rest of the week. In psoriasis the efficacy of this strategy is similar to that of continuous therapy even though the mean daily dose is significantly lower.<a class="elsevierStyleCrossRef" href="#bib0580">39</a> This regimen has produced promising results in pediatric patients with severe atopic dermatitis, enabling long-term therapy that avoids relapses<a class="elsevierStyleCrossRef" href="#bib0585">40</a> with less toxicity and a lower cumulative dose.Two of the main adverse effects that require dosage adjustment are kidney damage and arterial hypertension. If the creatinine level increases 30% over baseline on 2 consecutive reports 2 weeks apart, the dose should be lowered 25%. Hypertension would indicate the same dose adjustment. If the creatinine level or blood pressure returns to normal, ciclosporin treatment can continue at the lower dose. However, if these 2 variables remain elevated or continue to rise after 4 weeks on the lower dose of ciclosporin, the drug should be discontinued.<a class="elsevierStyleCrossRefs" href="#bib0565">36,37</a>Ciclosporin treatment can generally be suspended immediately without a rebound effect, although gradual weaning can lengthen the period of resolution before the next flare-up. Indications for discontinuing treatment are the failure to achieve good control of disease by 12 weeks, the development of severe adverse effects (neoplasms, infections), or a failure of blood pressure or creatinine levels to return to normal after a dose reduction. Cyclosporin should ideally be halted during pregnancy, unless symptoms make treatment necessary and there are no safer alternatives. In case treatment continues, the pregnancy should be considered high risk and followed closely. Treatment interruptions may be necessary in children so that vaccinations can be scheduled.AzathioprineAzathioprine is indicated for inflammatory diseases and the prevention of solid organ transplant rejection. This prodrug is promptly metabolized to 6-mercaptopurine, which is activated along various metabolic pathways by enzymes that form thioguanine nucleotides that are then incorporated into DNA, accounting for the drug's biological effects.<a class="elsevierStyleCrossRefs" href="#bib0590">41,42</a>Thiopurine methyltransferase (TPMT) is an enzyme that methylates various intermediate products, many of them inactive. In a small population percentage (0.3%) of individuals who are homozygous for one of the alleles associated with low or no activity, azathioprine would be contraindicated; in the 9% to 11% of heterozygotic individuals, activity is intermediate; finally, 89% to 91% of the population are homozygotic for an allele associated with high activity.<a class="elsevierStyleCrossRefs" href="#bib0590">41,43–45</a> Patients with high TPMT activity require higher doses of azathioprine to reach therapeutic levels than those with lower TPMT activity. However, low TPMT activity carries a higher risk of myelosuppression under treatment. Measurement of TPMT has been shown to be useful for establishing the safest and most effective dosage for each patient in both adults and children.<a class="elsevierStyleCrossRefs" href="#bib0600">43,46–48</a> Tests for TPMT are used increasingly often, and their cost has become more competitive. However, if testing is unavailable, azathioprine therapy can begin with low doses that are increased gradually under strict monitoring to detect early markers of myelosuppression.Other adverse effects, whether idiosyncratic or dose dependent, bear no relation to TPMT activity and may appear even when enzyme levels remain normal.<a class="elsevierStyleCrossRefs" href="#bib0590">41,47,49,50</a> There has even been a reported case of treated alopecia areata in which bone marrow suppression developed in the context of normal TPMT concentrations.<a class="elsevierStyleCrossRef" href="#bib0640">51</a> A recent meta-analysis identified a significant association between the presence of TPMT gene polymorphisms and general adverse effects of azathioprine therapy, bone marrow toxicity and gastric intolerance, although no association with hepatotoxicity was found.<a class="elsevierStyleCrossRef" href="#bib0645">52</a>The measurement and genotyping of glutathione-S-transferase have proven useful for assessing the risk of leukopenia in patients with inflammatory bowel disease, especially in oriental populations; however, it remains to be determined whether this marker is related to any other adverse effects of azathioprine therapy.<a class="elsevierStyleCrossRef" href="#bib0650">53</a>Patients mainly complain of bowel discomfort, with nausea, vomiting, diarrhea or abdominal pain, and these symptoms are the usual reason for discontinuing treatment. To avoid these adverse effects, doses can be fractioned and taken with food.<a class="elsevierStyleCrossRef" href="#bib0610">45</a>If gastrointestinal discomfort is severe or prolonged, hepatotoxicity, hypersensitivity, and pancreatitis must be ruled out.<a class="elsevierStyleCrossRef" href="#bib0635">50</a> In pancreatitis, symptoms and laboratory results usually improve rapidly when the drug is discontinued.The carcinogenic potential of azathioprine therapy is one of the greatest concerns. The risk is difficult to calculate and varies greatly between patient series. In addition to immunosuppression, azathioprine itself has been shown to cause photosensitivity, specifically in the UV-A spectrum; sun exposure therefore has a synergistic carcinogenic effect in azathioprine-treated patients.<a class="elsevierStyleCrossRef" href="#bib0595">42</a> Additional risk factors for developing skin cancer in these patients are prolonged treatment, high-dose regimens, and a fair-skinned phototype.<a class="elsevierStyleCrossRef" href="#bib0635">50</a> In addition to skin cancer, there is risk of lymphoma, and cases of Kaposi's angiosarcoma and renal cell carcinoma have been described.<a class="elsevierStyleCrossRef" href="#bib0655">54</a>Hypersensitivity to azathioprine can cause a variety of symptoms: fever, joint and muscle pain, nausea, hepatitis, interstitial nephritis, kidney failure, maculopapular rash, and panniculitis. A diagnostic challenge test can trigger a severe reaction, so it should be done in a hospital where the means for cardiopulmonary resuscitation are at hand. In such cases, 6-mercaptopurine therapy would be a better tolerated alternative.<a class="elsevierStyleCrossRef" href="#bib0590">41</a>The risk of infection also increases. Viral warts, molluscum contagiosum, folliculitis, and impetigo are common in treated children.<a class="elsevierStyleCrossRef" href="#bib0660">55</a>Mycophenolate Mofetil and Mycophenolate Sodium SaltThe selective, reversible inhibition of inosine monophosphate dehydrogenase type 2 by mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) interferes with the purine synthesis pathway of T and B cells, but not other cells.<a class="elsevierStyleCrossRefs" href="#bib0665">56,57</a> MMF is a prodrug that becomes mycophenolic acid once digested. The MPS salt is sold in an enteric-coated form.<a class="elsevierStyleCrossRef" href="#bib0675">58</a>MMF or MPS therapy is indicated in heart, liver, or kidney transplanted patients to prevent acute rejection. No approved dermatologic uses are listed in the product summaries.<a class="elsevierStyleCrossRef" href="#bib0445">12</a>However, the use of these drugs has been explored in various inflammatory diseases because liver and kidney toxicity is higher with alternative immunosuppressants.Onset of action, which is slower than in glucocorticoid or ciclosporin treatment, takes at least 1 month and sometimes 3 to 4 months. This therapeutic option, therefore, is for maintenance of effect,<a class="elsevierStyleCrossRef" href="#bib0675">58</a> either by itself or as a corticosteroid-sparing strategy.Good outcomes have been reported in pyoderma gangrenosum<a class="elsevierStyleCrossRef" href="#bib0675">58</a> and severe atopic dermatitis with both MMF<a class="elsevierStyleCrossRef" href="#bib0665">56</a> and MPS<a class="elsevierStyleCrossRefs" href="#bib0680">59,60</a> in both adults and children.<a class="elsevierStyleCrossRef" href="#bib0690">61</a> Positive results have also been reported in pemphigus vulgaris,<a class="elsevierStyleCrossRef" href="#bib0695">62</a> collagenosis,<a class="elsevierStyleCrossRefs" href="#bib0700">63,64</a> chronic idiopathic urticaria,<a class="elsevierStyleCrossRef" href="#bib0710">65</a> and lichen planus and sarcoidosis.<a class="elsevierStyleCrossRef" href="#bib0705">64</a> The results in psoriasis have been less positive,<a class="elsevierStyleCrossRef" href="#bib0715">66</a> although one randomized clinical trial found that efficacy was statistically similar to that of methotrexate.<a class="elsevierStyleCrossRef" href="#bib0720">67</a> Evidence generally comes from single case reports or case series. Hardly any high quality randomized clinical trials have been published.Immunosuppressant doses of these drugs vary in inflammatory diseases; doses of 500mg to 1g of MMF are given every 12hours (or 720mg of MPS every 12 hours). If a daily dose of 2g of MMF is reached without response, plasma levels of mycophenolic acid should be measured to rule out poor adherence or decide whether to increase the dose if absorption is low.<a class="elsevierStyleCrossRef" href="#bib0725">68</a> Plasma levels vary greatly between patients and, curiously, between diseases. Mycophenolic acid plasma trough level has been shown to be a poor predictor of the effectiveness and safety of MMF therapy.A great advantage of MMF over other immunosuppressants is its good tolerance and safety profile, particularly with regard to renal toxicity, hepatotoxicity, and neurotoxicity.The most commonly reported adverse effects (in 12%–36%) involve the digestive system<a class="elsevierStyleCrossRef" href="#bib0700">63</a> and include diarrhea, nausea, vomiting, abdominal pain, and soft stools. These effects are dose dependent and rarely oblige discontinuance of treatment. Transaminase levels rise in some patients, but no clinical impact or clear hepatotoxicity has been reported. Enteric-coated MPS is better tolerated.Leukopenia is observed more often than anemia or thrombocytopenia, and again, the relationship is dose dependant. At dosages of 3g/d, this adverse effect develops in 34% of patients.<a class="elsevierStyleCrossRef" href="#bib0705">64</a> If neutrophil counts fall below 1300 cells/mL, discontinuance is indicated. Red cell dysplasia has been reported, particularly in transplanted patients.<a class="elsevierStyleCrossRef" href="#bib0725">68</a> These hematologic effects usually improve quickly when the drug is discontinued or the dose is reduced.Urinary tract symptoms (dysuria, urgency, frequent urination, sterile pyuria, or hematuria) are not unusual, especially at the beginning of treatment. They usually improve after a year.Conclusions about the risk of infection and neoplasia vary greatly in the literature. Published studies are difficult to compare, given that transplanted patients tend to receive higher doses and take more concurrent immunosuppressants than patients who have inflammatory diseases.CyclophosphamideCyclophosphamide is an alkylating agent that interferes with DNA replication by attaching an alkyl group to the guanine base,<a class="elsevierStyleCrossRef" href="#bib0730">69</a> causing cell death. The drug targets T cells and, to a lesser degree, B cells.<a class="elsevierStyleCrossRef" href="#bib0735">70</a> The usual oral dosage is 1 to 2mg/kg/d; the intravenous dosage is 500–1000mg/m2 of body surface every month.Because this potent drug has adverse effects, it is reserved for particularly severe cases. Dermatologic indications are autoimmune bullous diseases (especially pemphigus vulgaris and pemphigus foliaceous), autoimmune systemic vasculitis; severe cutaneous lupus erythematosus; cutaneous manifestations of systemic sclerosis; and cutaneous T-cell lymphoma.<a class="elsevierStyleCrossRefs" href="#bib0740">71,72</a>A higher cumulative daily dose increases the risk of toxicity in oral administration. Therefore, different therapeutic regimens have attempted to minimize that risk. Among the strategies tried are monthly intravenous infusions either alone or combined with low-dose oral therapy, and a single immunoablative high dose without stem-cell rescue. The efficacy of these alternative approaches seems to differ little from that of daily oral doses.<a class="elsevierStyleCrossRefs" href="#bib0735">70–76</a> Intravenous pulse therapy, however, leads to a lower cumulative dose and seems to be safer.<a class="elsevierStyleCrossRef" href="#bib0770">77</a>Digestive symptoms such as nausea, vomiting, diarrhea, and stomatitis are common. Nausea is reported more in pulse therapy than oral treatment. Antiemetic prophylaxis is recommended.Myelosuppression is an acute, dose-dependent adverse effect that usually presents with leukopenia. Monitoring is required to adjust the dose to keep the white blood cell count above 3500 to 4000 cells/mL. If the neutrophil count falls to dangerously low levels, granulocytic-colony-stimulating factors may have to be given.<a class="elsevierStyleCrossRef" href="#bib0770">77</a> Treatment with cotrimoxazole or dapsone is recommended to guard against Pneumocystis jirovecii infection.<a class="elsevierStyleCrossRef" href="#bib0750">73</a> Between 9% and 15% of patients had to be hospitalized for severe herpes zoster infection in some series.<a class="elsevierStyleCrossRef" href="#bib0740">71</a> As in the context of other immunosuppressant therapies, pneumococcus as well as regular influenza vaccinations are indicated.Hemorrhagic cystitis is a typical side effect of cyclophosphamide therapy. The incidence ranges from 8% to 41%, depending on dose, and oral intake seems to be associated with greater risk than pulse treatments. This complication seems to be caused by urinary secretion of a metabolite (acrolein) that irritates the urothelium. Preventive measures include drinking plenty of liquids, not taking the drug at night, and voiding the bladder before going to bed so that acrolein does not remain in contact with the mucosal tissue all night. Intravenous pulse infusion should be accompanied by intense fluid therapy to force diuresis. Adjuvant treatment with sodium 2-mercaptoethane sulfonate (Mesna), which binds to and deactivates acrolein, is also an option. This drug is given immediately after and again 4 and 8hours after cyclophosphamide, and each infusion should contain a dose that is 20% of the cyclophosphamide dose. In other words, after a dose of 1000mg of cyclophosphamide, the patient should receive 3 doses containing 200mg of Mesna each.The other adverse effects of cyclophosphamide involve gonadal toxicity. Oral intake in particular seems to lead to premature ovarian failure, azoospermia, menstrual irregularity, and potentially irreversible infertility. The use of testosterone in men and gonadotropin-releasing hormone analogs in women is a subject of debate. Cyclophosphamide should therefore be avoided in patients of reproductive age. If it must be prescribed, the patient should be referred for reproductive counseling to assess the advisability of cryopreservation.Conflicts of InterestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres963174" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec933494" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres963173" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec933495" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Pretreatment Tests and Vaccinations" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Practical Aspects of Immunosuppressant Therapy" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Methotrexate" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Ciclosporin" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Azathioprine" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Mycophenolate Mofetil and Mycophenolate Sodium Salt" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Cyclophosphamide" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of Interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-18" "fechaAceptado" => "2017-05-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec933494" "palabras" => array:6 [ 0 => "Methotrexate" 1 => "Ciclosporin" 2 => "Cyclophosphamide" 3 => "Azathioprine" 4 => "Mycophenolate" 5 => "Immunosuppression" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec933495" "palabras" => array:6 [ 0 => "Metotrexato" 1 => "Ciclosporina" 2 => "Ciclofosfamida" 3 => "Azatioprina" 4 => "Micofenolato" 5 => "Inmunosupresión" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The treatment of inflammatory and autoimmune diseases is challenging because of their frequency and complexity. Treatment of these diseases is based on the suppression of the patient's immune system using corticosteroids, corticosteroid-sparing immunosuppressive agents, and biologic drugs, making an understanding of the management of immunosuppressive therapy essential. Before an immunosuppressive agent is prescribed, a study must be carried out to identify contraindications, detect latent infections, and determine the most appropriate dose. During treatment, regular monitoring is required to detect adverse effects. The clinician must be familiar with the time lag between start of treatment and onset of the immunosuppressive effect as well as the maximum recommended duration of treatment and cumulative dose for each drug. As dermatologists we are accustomed to using these immunosuppressive agents, but we should have a good knowledge of the guidelines for their use and the monitoring required in each case if we are to reduce variability and avoid potentially serious adverse effects." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las enfermedades inflamatorias y autoinmunes constituyen un desafío terapéutico por frecuencia y complejidad. Su tratamiento se basa en la inmunosupresión del paciente con glucocorticoides, inmunosupresores ahorradores de corticoides y fármacos biológicos, siendo imprescindible por tanto conocer su manejo. Cuando se va a pautar un inmunosupresor es necesario realizar un estudio previo para detectar contraindicaciones, infecciones latentes o determinar la dosis más adecuada del fármaco. Durante el tratamiento se deben realizar controles periódicos para detectar efectos secundarios. Cada fármaco tiene un tiempo de inicio de acción que es preciso conocer, así como una duración o dosis acumulada máxima recomendada. Los dermatólogos estamos habituados al uso estos fármacos inmunosupresores, pero es necesario tener claras las pautas y los controles necesarios con cada uno, para disminuir la variabilidad y evitar efectos adversos potencialmente graves." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Leis-Dosil V, Prats-Caelles I. Practical Management of Immunosuppressants in Dermatology. Actas Dermosifiliogr. 2018;109:24–34." ] ] "multimedia" => array:7 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: ACTH, adrenocorticotropic hormone; GFR, glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; P3NP, procollagen type III N-terminal peptide; TPMT, thiopurine methyltransferase." "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ciclosporin \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Azathioprine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mycophenolate Mofetil and Mycophenolate Sodium \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cyclophosphamide \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Complete blood count, including differential white blood cell counts Biochemistry, including glucose, ion concentrations, kidney function, liver function (transaminase, alkaline phosphatase, bilirubin, albumin), lipids, uric acid Serology for HBV, HBC, and HIV Full vaccination coverage Tuberculosis screening (Mantoux test or quantitative interferon gamma release assay) Pregnancy test in women of childbearing age </td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindicated if total bilirubin concentration is >5mg/dL Urinalysis Chest x-ray P3NP level \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Estimated GFR to dermine renal function and adjust dosage. Blood pressure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TPMT level \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chest x-ray (consider) Urinalysis. Rule out adrenal insufficiency (baseline cortisol and ACTH levels, stimulation test to measure cortisol before and after injection of 250μg of ACTH). Spermogram and sperm banking prior to treatment. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631734.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Complementary Tests to Order Before Starting Immunosuppressant Therapy." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: IV, intravenous; TPMT, thiopurine methyltransferase.Source: Summaries of product characteristics posted by the Spanish Agency for Medicines and Health Products. Available from https://www.aemps.gob.es/cima/fichasTecnicas.do?metodo=detalleForm" "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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ciclosporin \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Azathioprine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mycophenolate Mofetil and Mycophenolate Sodium \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cyclophosphamide \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dermatologic indications in the summary of product characteristics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Psoriasis. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Psoriasis. Atopic dermatitis. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Systemic lupus erythematosus. Dermatomyositis. Pemphigus vulgaris. Pyoderma gangrenosum. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">“Life-threatening” autoimmune diseases. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommended dosage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">From 5 to a maximum of 25mg/wk. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5–5mg/kg/d. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–2.5mg/kg/d (adjust for TPMT level). Maximum dosage 200mg/d. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mycophenolate mofetil: 1–2g/d in 2 doses. Mycophenolate sodium: 1080–1440mg/d. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral: 1–2mg/kg/d; maximum, 2.5mg/kg/d. IV: 500–1000mg/m2 of body surface per month. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Onset of action \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Slow, 4–8wk. Wait 12wk before declaring treatment failure. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rapid, 2–4wk. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">May take months. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Most responders improve in 4wk; some need 3mo. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rapid, from 2 to 16wk, around 5wk on average. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Maximum duration of treatment recommended \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Assess liver toxicity at cumulative doses of 1500mg. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to course of disease. Carcinogenic risk after10 y. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">According to tolerance and response. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Significant cumulative toxicity, but can be maintained. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631731.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Basic Features of Immunosuppressants to Know When Selecting a Therapy." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: MCV, mean corpuscular volume; NSAID, nonsteroidal anti-inflammatory drug; PIIINP, procollagen type III N-terminal peptide." "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5mg tablets. Prefilled syringes (7.5, 10, 15, 20, 25, and 30mg). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Initial dosing: 7.5–15mg/wk. Schedule a specific day of the week to avoid confusion. Gradually increase the dose as needed. Avoid exceeding 20mg/wk. Supplement with folic acid, 5–15mg/wk taken 24–48h after the methotrexate dose. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complete blood count, including ion concentration and kidney and liver function profiles. Increase the dose after 1 wk and then after 2, 4, 6, 10, 14, and 18wk; then after 3 mo. PIIINP every 3 mo. Elastography (FibroScan) if an abnormal PIIINP concentration is found more than twice. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pregnancy (and men should not father a child until 3 mo after interrupting treatment). Severe liver disease. Marked cytopenia. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Live or attenuated virus vaccines, cotrimoxazole, phenytoin, ciclosporin, azathioprine, NSAIDs. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pregnancy. Significant, sustained increase in PIINP concentration. Sustained MCV increase that does not resolve with folic acid. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631732.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Practical Aspects of Treatment With Methotrexate." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: ACE, angiotensin converting enzyme." "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Capsules of 25, 50, and 100mg. Oral solution, 100mg/mL. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Initial dosing: 2.5–3.5mg/kg/d (calculated based on ideal weight, not actual weight, to avoid overdosing). Maintenance at the lowest effective dose. Do not exceed 5mg/kg/d. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Blood pressure weekly, always under the same conditions. The patient should record readings and bring them to medical visits. Laboratory tests: Complete blood count, including ion concentrations, kidney and liver function profiles, uric acid level, and urinalysis. Repeat every 2wk for the first 3mo, then monthly. Drug levels can be measured if interactions or poor adherence is suspected. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Active infections. Neoplasms (rule out basal cell carcinoma). Uncontrolled arterial hypertension. No not use phototherapy, due to increased risk of tumors. Kidney failure (monitor renal function). Liver failure, cirrhosis (avoid ciclosporin or use low doses). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Numerous interactions with drugs metabolized by cytochrome P450 and CYP34A \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">After 1y of therapy (recommended). Hypertension detected on 2 measurements after which the dosage is lowered 25%; if there is no improvement, add an antihypertensive medication (a dihydropyridine calcium channel blocker, an ACE inhibitor, or an angiotensin-II receptor blocker); if no improvement, discontinue ciclosporin. Kidney toxicity: if creatinine clearance is impaired according to 2 measurements within 2 wk, lower the dose 25%; if there is improvement, maintain ciclosporin at the lower dose; if no improvement, discontinue. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631729.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Practical Aspects of Treatment With Ciclosporin." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: ACE, angiotensin converting enzyme; MCV, mean corpuscular volume; TPMT, thiopurine methyltransferase." "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tablets of 50mg. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.5–3mg/kg/d. Adjust for TPMT activity. Start at a low dose and increase according to tolerance and response. If TPMT testing is unavailable, start with a low dose (50mg/d) and gradually increase with strict follow-up (complete blood count). If MCV increases less than 3fL in 3 mo, the dosage can be increased 0.5mg/kg/d. If MCV increases >8fL, lower the dosage 0.5mg/kg/d and repeat testing, including for folic acid and vitamin B12. Divide the daily dose in 2 fractions to improve gastrointestinal tolerance. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complete blood count, kidney function, liver function at 1, 2, 3, 4, 6, 8, 12, 16, and 20 wk. Then, every 3 mo. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Allergy to azathioprine or 6-mercaptopurine. Neoplasms (current). TPMT absent or <5IU/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mycophenolate mofatil, mycophenolate sodium. Live or attenuated virus vaccines. Allopurinol. Sulfasalazine. Cotrimoxazole. ACE inhibitors. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Breastfeeding. Assess risks-benefits during pregnancy. Hypersensitivity reaction. Pancreatitis. Hepatotoxicity. Myelotoxicity. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631735.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Practical Aspects of Treatment With Azathioprine." ] ] 5 => array:8 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at6" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: MMF, mycophenolate mofetil; MPS, mycophenolate sodium." "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPS: enteric-coated tablets of 180 and 360mg. MMF: capsules of 250mg, coated tablets of 500mg, powder for oral suspension of 1g/5mL, vials of 500mg. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPS: 720mg/12h. MMF: start with 250–500mg/12h and increase every wk until a dosage of 1g/12h can be maintained. Never administer a bolus dose intravenously. Capsules and tablets should be swallowed whole with a glass of water. MMF can be taken with or without food. MPS can also be ingested with or without food, but once a habit is started it should be continued. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complete blood count every 2wk in the first month, then monthly for 3mo, then every 2mo. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pregnancy, breastfeeding, drug allergy. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Azathioprine, ciclosporin, live virus and attenuated virus vaccines, aciclovir, colestyramine, tacrolimus, rifampicin, antacids. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Severe leukopenia (<1300cells/mL) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631733.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Practical Aspects of Treatment With Mycophenolate Mofetil and Mycophenolate Sodium." ] ] 6 => array:8 [ "identificador" => "tbl0035" "etiqueta" => "Table 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at7" "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tablets of 50mg. Vials of 200 and 1000mg in solution. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral: 50–100mg/d; can be increased to 2mg/kg/d in severe cases. The tablet must be taken whole, neither chewed nor crushed. To minimize side effects, take in single doses in the morning and drink plenty of liquids (3L/d). Empty bladder before going to sleep. Take antiemetics if necessary. Intravenous pulse therapy: starting dose, 500mg/m2; then 750mg/m2; then, if tolerated, 1000mg/m2. Administer intravenous fluids in abundance. Prescribe antiemetics, possibly before cyclophosphamide. Evaluate possible use of intravenous infusion. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral therapy Complete blood count every 7–14d for 1mo on initiating treatment and after any dosage changes. Then every 1–3mo. Adjust dosage to maintain white blood cell count >4000cells/mL. Urinalysis every 1–3mo. Urine cytology 1–2times/y. Cytoscopy if blood in urine or abnormal cytology findings. Liver workup every 3mo. Pregnancy test. Intravenous pulse therapy: Complete blood count immediately after an infusion and 10–14d later. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absolute: Pregnancy and breastfeeding, drug allergy, myelosuppression, history of bladder cancer. Relative: active infection, liver or kidney failure. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Succinylcholine, anticholinergic agents, allopurinol, busulfan, chlorpromazine, ciprofloxacin, fluconazole, thiotepa \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bladder cancer, acute cardiotoxicity. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1631730.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Practical Aspects of Treatment With Cyclophosphamide." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:77 [ 0 => array:3 [ "identificador" => "bib0390" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Practical guidelines for the use of steroid-sparing agents in the treatment of chronic pruritus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.E. Cotes" 1 => "R.A. Swerlick" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/dth.12026" "Revista" => array:6 [ "tituloSerie" => "Dermatol Ther" "fecha" => "2013" "volumen" => "26" "paginaInicial" => "120" "paginaFinal" => "134" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23551369" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0395" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Grupo de trabajo de vacunación de adultos de la ponencia de programas y registro de vacunaciones. Vacunación en adultos. Madrid: Ministerio de Sanidad y Consumo; 2004." ] ] ] 2 => array:3 [ "identificador" => "bib0400" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vaccination in patients with primary immune deficiency, secondary immune deficiency and autoimmunity with immune regulatory abnormalities" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.M. Eibl" 1 => "H.M. Wolf" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2217/IMT.15.74" "Revista" => array:6 [ "tituloSerie" => "Immunotherapy" "fecha" => "2015" "volumen" => "7" "paginaInicial" => "1273" "paginaFinal" => "1292" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26289364" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0405" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Executive Summary: 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.G. Rubin" 1 => "M.J. Levin" 2 => "P. Ljungman" 3 => "E.G. Davies" 4 => "R. Avery" 5 => "M. 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Practical Dermatology

Practical Management of Immunosuppressants in Dermatology

Manejo práctico de inmunosupresores en dermatología

V.M. Leis-Dosil

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vmanuel.leis@salud.madrid.org

Corresponding author.

, I. Prats-Caelles

Sección de Dermatología, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, España

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Dermatologic autoimmune or inflammatory diseases are usually managed with immunosuppressants&#46; Care must be taken to find a point of balance that attenuates the abnormal inflammatory response while causing the least possible immunosuppression&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The prescriber must be aware of each immunosuppressant&#39;s unique time to onset of action&#44; level of acute toxicity&#44; and dosage regimens&#46; An intense&#44; rapid response is sometimes warranted&#44; but a goal in other circumstances might be a treatment that can be followed over the long term&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">This review deals with classic immunosuppressants&#46; Neither glucocorticoids nor biologics will be discussed&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pretreatment Tests and Vaccinations</span><p id="par0020" class="elsevierStylePara elsevierViewall">Before suppressing a patient&#39;s immune response&#44; information is required for ruling out contraindications&#44; tailoring the dosage&#44; and planning measures to reduce inherent risk&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Certain laboratory tests are needed for prescribing any of these drugs&#44; but particular immunosuppressants also have specific requirements<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">1</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Because vaccination coverage should be on record for all patients&#44; serology is included in the test battery&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">2&#8211;5</span></a> If the patient&#39;s clinical condition permits&#44; required vaccinations or booster doses should be scheduled at least 2 weeks before immunosuppressant therapy starts&#46; If vaccination is not feasible beforehand&#44; it should not be undertaken until at least 3 months after treatment stops given that live virus vaccines carry the risk of infection&#44; and immunization may not be achieved if inactivated viruses are used&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Vaccination against varicella should be tailored to the individual&#46; If a pediatric vaccination schedule must be followed&#44; immunosuppressants should be interrupted 2 weeks before vaccination and not restarted until 2 weeks afterwards&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Two types of pneumococcal vaccines are available&#58; the 23-valent polysaccharide &#40;PPSV23&#41; and 13-valent conjugate &#40;PCV13&#41; versions&#46; Spanish health authorities stipulate a sequential vaccination schedule for patients on immunosuppressants&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">7</span></a> The schedule starts with a dose of PCV13 before treatment and is followed by a dose of PPSV23 at least 8 weeks later&#46; If the patient is already under treatment&#44; these criteria should be applied when the first consultation takes place&#46; A booster dose of PPSV23 should be given at 5 years&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Patients on immunosuppressants should receive the same influenza vaccination produced for the general population every year&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Certain factors affect the choice of one immunosuppressant drug &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; over another&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">whether or not the patient has a medical history that includes a contraindication for a particular immunosuppressant or new testing reveals such a contraindication&#44;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">whether or not the drug&#39;s summary of product characteristics includes the patient&#39;s disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">9&#8211;13</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">whether or not an intense&#44; rapid response is required&#44;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">or alternatively&#44; whether the prescriber seeks a maintenance of effect over a long course of treatment&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Practical Aspects of Immunosuppressant Therapy</span><p id="par0075" class="elsevierStylePara elsevierViewall">Once an immunosuppressant is selected&#44; it must be fully understood if we are to achieve the best results for our patient&#46; For practical purposes we will analyze the main aspects relevant to managing the immunosuppressants most often prescribed by dermatologists &#40;<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3&#8211;7</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methotrexate</span><p id="par0080" class="elsevierStylePara elsevierViewall">Methotrexate&#44; an antimetabolite analog of folic acid&#44; inhibits dihydrofolate reductase&#46; It is unquestionably one of the most often prescribed immunosuppressants in dermatology&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">14</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Although psoriasis is the only indication listed in the product summary&#44;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">13&#44;15&#44;16</span></a> many studies have supported this drug&#39;s use in other conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">17</span></a> Some examples are autoimmune bullous diseases<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">18</span></a>&#59; severe adult atopic dermatitis<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">19</span></a>&#59; alopecia areata<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">20</span></a>&#59; chronic urticaria<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">21</span></a>&#59; cutaneous lupus erythematosus<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">22&#44;23</span></a>&#59; sarcoidosis&#44; scleroderma&#44; lymphomatoid papulosis and other lymphoproliferative disorders<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">17&#44;24</span></a>&#59; and keratoacanthomas&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">25</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Methotrexate is available in tablets of 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg and syringes prefilled with doses ranging from 7&#46;5 to 30<span class="elsevierStyleHsp" style=""></span>mg &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Oral administration is much more economical than parenteral injection and the bioequivalence is similar&#44; at least up to a weekly dose of 17&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">14&#44;16</span></a> However&#44; gastrointestinal symptoms are common with oral intake&#44; and injections are therefore recommended when the dose exceeds 15<span class="elsevierStyleHsp" style=""></span>mg to prevent digestive intolerance&#46; Parenteral administration is also advisable when the patient is at risk of confusing doses or adherence is poor&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">26</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The patient must be told that the drug is taken or injected once a week&#44; not daily&#44; if serious side effects are to be avoided&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">17&#44;26</span></a> It is good practice to establish a particular time each week that takes into consideration that the dose will be followed by days of discomfort and that samples for laboratory tests must be collected the day before dosing&#44; as long as possible before the drug is actually taken&#46; The entire oral dose can be ingested at once or in 2 or 3 fractions separated by 12<span class="elsevierStyleHsp" style=""></span>hours&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">A test dose is not currently considered necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">27</span></a> A starting dosage of 7&#46;5 to 15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk should be given and gradually increased until the response is satisfactory&#46; Increases of 2&#46;5 to 5<span class="elsevierStyleHsp" style=""></span>mg can be tried every 4 to 6 weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">17&#44;19</span></a> Responders usually improve at 4<span class="elsevierStyleHsp" style=""></span>weeks&#44; but we have waited up to 12<span class="elsevierStyleHsp" style=""></span>weeks before deciding that treatment has failed&#46; A regimen of 15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk is usually effective&#46; The approach should be reviewed if 25<span class="elsevierStyleHsp" style=""></span>mg&#47;wk is exceeded&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The strategy to follow is similar in psoriasis and other diseases&#46; In autoimmune bullous diseases&#44; for example&#44; certain patients are nonresponders &#40;13&#37; in pemphigus vulgaris&#44; 4&#37; in bullous pemphigoid&#41;&#44; and no data on predictors of failure are available&#46; On the other hand&#44; mortality due to serious infection is considerable &#40;3&#46;7&#37; in pemphigus vulgaris&#44; 2&#46;5&#37; in bullous pemphigoid&#41;&#46; Nonetheless methotrexate therapy remains a good corticosteroid-sparing strategy&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">18</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Methotrexate should be accompanied by folic or folinic acid supplementation&#44; which significantly reduces adverse effects on the liver and nonsignificantly improves effects on mucosal&#44; gastrointestinal and blood tissues but does not prevent the development of pulmonary fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">26&#44;28</span></a> Some studies consider supplementation to be contraindicated in the interest of efficacy&#44; but a reduction in methotrexate&#39;s effect with folic acid is fairly unlikely<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">28</span></a> because the 2 drugs promote the anti-inflammatory action of adenosine through different mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">16</span></a> Folic acid and folinic acid do not appear to differ in effectiveness&#44; and the former is less costly&#46; Dosage regimens are debated&#46; They vary from 5 to 30<span class="elsevierStyleHsp" style=""></span>mg&#47;wk unless other conditions requiring folic or folinic acid supplementation are present&#44; in which case 5<span class="elsevierStyleHsp" style=""></span>mg&#47;week taken 24 to 48<span class="elsevierStyleHsp" style=""></span>hours after the methotrexate dose should be sufficient&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">26</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">One of the main adverse effects of methotrexate is liver fibrosis&#46; One systematic review found that the risk for fibrosis increased 22&#37; in patients with methotrexate-treated psoriasis&#59; however&#44; risk was not significantly related to duration of therapy or cumulative dose&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">29</span></a> The authors therefore concluded that fibrosis develops only in a certain subgroup of patients whose characteristics could not be determined due to the low quality of evidence provided by the studies reviewed&#46; It is likely that comorbid conditions such as obesity or alcohol intake exacerbate risk in some&#46; A noninvasive means for detecting fibrosis without resorting to liver biopsy is required&#46; The most widely studied approaches are the measurement of biomarkers &#40;eg&#44; procollagen type III N-terminal peptide<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">30</span></a>&#41; and the use of imaging techniques such as elastography &#40;eg&#44; FibroScan&#41;&#46; One meta-analysis showed that these 2 techniques applied individually have low discriminatory power in screening&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">31</span></a> However&#44; combining various biomarkers &#40;eg&#44; in the enhanced liver fibrosis panel&#41; or biomarkers and imaging may be more useful&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Ciclosporin</span><p id="par0120" class="elsevierStylePara elsevierViewall">Ciclosporin is a calcineurin inhibitor that acts on T cells&#46;The summary of product characteristics for this drug lists psoriasis and atopic dermatitis as the dermatologic indications&#46; However&#44; ciclosporin has been used to effectively treat Stevens&#8211;Johnson syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">32</span></a> lichen planus and lichen planopilaris&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">33</span></a> pyoderma gangrenosum&#44; chronic urticaria&#44; autoimmune blistering diseases&#44; suppurative hidradenitis&#44; and more&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The great advantage of ciclosporin is its rapid onset of action&#46; Good control of disease can be achieved in a few months with a short treatment cycle&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Dose regimens range from 2&#46;5 to 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">36</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Although ciclosporin is lipophilic&#44; it is important to remember that distribution is mainly through lean tissues&#46; Therefore&#44; when the real weight of obese patients is used to calculate the dosage&#44; the concentration of the circulating drug will be elevated and there is risk of toxicity&#46; Consequently&#44; the dose should be calculated based on the patient&#39;s ideal weight&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">37</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The daily dose is usually divided into 2 fractions&#46; Taking ciclosporin before food intake has been shown to facilitate absorption&#44; allow for lower doses and favor more even&#44; predictable pharmacokinetics&#46; Ciclosporin should therefore be taken before breakfast and before the evening meal&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">38</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">It is generally not recommended to prolong treatment beyond 1 year because long treatment cycles carry greater risk of toxicity&#46; However&#44; strategies that allow treatment to be maintained as long as possible have been explored&#46; The 2 usual approaches&#44; particularly in psoriasis&#44; involve rotations and combinations that allow for lower daily doses&#46; Weekend pulse therapy is another possibility once a conventional regimen has acheived control of disease&#46; This regimen consists of prescribing a maintenance dose of up to 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d for 2 consecutive days per week and resting for the rest of the week&#46; In psoriasis the efficacy of this strategy is similar to that of continuous therapy even though the mean daily dose is significantly lower&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">39</span></a> This regimen has produced promising results in pediatric patients with severe atopic dermatitis&#44; enabling long-term therapy that avoids relapses<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">40</span></a> with less toxicity and a lower cumulative dose&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Two of the main adverse effects that require dosage adjustment are kidney damage and arterial hypertension&#46; If the creatinine level increases 30&#37; over baseline on 2 consecutive reports 2 weeks apart&#44; the dose should be lowered 25&#37;&#46; Hypertension would indicate the same dose adjustment&#46; If the creatinine level or blood pressure returns to normal&#44; ciclosporin treatment can continue at the lower dose&#46; However&#44; if these 2 variables remain elevated or continue to rise after 4 weeks on the lower dose of ciclosporin&#44; the drug should be discontinued&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">36&#44;37</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Ciclosporin treatment can generally be suspended immediately without a rebound effect&#44; although gradual weaning can lengthen the period of resolution before the next flare-up&#46; Indications for discontinuing treatment are the failure to achieve good control of disease by 12 weeks&#44; the development of severe adverse effects &#40;neoplasms&#44; infections&#41;&#44; or a failure of blood pressure or creatinine levels to return to normal after a dose reduction&#46; Cyclosporin should ideally be halted during pregnancy&#44; unless symptoms make treatment necessary and there are no safer alternatives&#46; In case treatment continues&#44; the pregnancy should be considered high risk and followed closely&#46; Treatment interruptions may be necessary in children so that vaccinations can be scheduled&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Azathioprine</span><p id="par0155" class="elsevierStylePara elsevierViewall">Azathioprine is indicated for inflammatory diseases and the prevention of solid organ transplant rejection&#46; This prodrug is promptly metabolized to 6-mercaptopurine&#44; which is activated along various metabolic pathways by enzymes that form thioguanine nucleotides that are then incorporated into DNA&#44; accounting for the drug&#39;s biological effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">41&#44;42</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Thiopurine methyltransferase &#40;TPMT&#41; is an enzyme that methylates various intermediate products&#44; many of them inactive&#46; In a small population percentage &#40;0&#46;3&#37;&#41; of individuals who are homozygous for one of the alleles associated with low or no activity&#44; azathioprine would be contraindicated&#59; in the 9&#37; to 11&#37; of heterozygotic individuals&#44; activity is intermediate&#59; finally&#44; 89&#37; to 91&#37; of the population are homozygotic for an allele associated with high activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">41&#44;43&#8211;45</span></a> Patients with high TPMT activity require higher doses of azathioprine to reach therapeutic levels than those with lower TPMT activity&#46; However&#44; low TPMT activity carries a higher risk of myelosuppression under treatment&#46; Measurement of TPMT has been shown to be useful for establishing the safest and most effective dosage for each patient in both adults and children&#46;<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">43&#44;46&#8211;48</span></a> Tests for TPMT are used increasingly often&#44; and their cost has become more competitive&#46; However&#44; if testing is unavailable&#44; azathioprine therapy can begin with low doses that are increased gradually under strict monitoring to detect early markers of myelosuppression&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Other adverse effects&#44; whether idiosyncratic or dose dependent&#44; bear no relation to TPMT activity and may appear even when enzyme levels remain normal&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">41&#44;47&#44;49&#44;50</span></a> There has even been a reported case of treated alopecia areata in which bone marrow suppression developed in the context of normal TPMT concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">51</span></a> A recent meta-analysis identified a significant association between the presence of TPMT gene polymorphisms and general adverse effects of azathioprine therapy&#44; bone marrow toxicity and gastric intolerance&#44; although no association with hepatotoxicity was found&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">52</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The measurement and genotyping of glutathione-S-transferase have proven useful for assessing the risk of leukopenia in patients with inflammatory bowel disease&#44; especially in oriental populations&#59; however&#44; it remains to be determined whether this marker is related to any other adverse effects of azathioprine therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">53</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Patients mainly complain of bowel discomfort&#44; with nausea&#44; vomiting&#44; diarrhea or abdominal pain&#44; and these symptoms are the usual reason for discontinuing treatment&#46; To avoid these adverse effects&#44; doses can be fractioned and taken with food&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">45</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">If gastrointestinal discomfort is severe or prolonged&#44; hepatotoxicity&#44; hypersensitivity&#44; and pancreatitis must be ruled out&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">50</span></a> In pancreatitis&#44; symptoms and laboratory results usually improve rapidly when the drug is discontinued&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The carcinogenic potential of azathioprine therapy is one of the greatest concerns&#46; The risk is difficult to calculate and varies greatly between patient series&#46; In addition to immunosuppression&#44; azathioprine itself has been shown to cause photosensitivity&#44; specifically in the UV-A spectrum&#59; sun exposure therefore has a synergistic carcinogenic effect in azathioprine-treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">42</span></a> Additional risk factors for developing skin cancer in these patients are prolonged treatment&#44; high-dose regimens&#44; and a fair-skinned phototype&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">50</span></a> In addition to skin cancer&#44; there is risk of lymphoma&#44; and cases of Kaposi&#39;s angiosarcoma and renal cell carcinoma have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">54</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Hypersensitivity to azathioprine can cause a variety of symptoms&#58; fever&#44; joint and muscle pain&#44; nausea&#44; hepatitis&#44; interstitial nephritis&#44; kidney failure&#44; maculopapular rash&#44; and panniculitis&#46; A diagnostic challenge test can trigger a severe reaction&#44; so it should be done in a hospital where the means for cardiopulmonary resuscitation are at hand&#46; In such cases&#44; 6-mercaptopurine therapy would be a better tolerated alternative&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">41</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">The risk of infection also increases&#46; Viral warts&#44; molluscum contagiosum&#44; folliculitis&#44; and impetigo are common in treated children&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Mycophenolate Mofetil and Mycophenolate Sodium Salt</span><p id="par0200" class="elsevierStylePara elsevierViewall">The selective&#44; reversible inhibition of inosine monophosphate dehydrogenase type 2 by mycophenolate mofetil &#40;MMF&#41; or mycophenolate sodium &#40;MPS&#41; interferes with the purine synthesis pathway of T and B cells&#44; but not other cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">56&#44;57</span></a> MMF is a prodrug that becomes mycophenolic acid once digested&#46; The MPS salt is sold in an enteric-coated form&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">58</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">MMF or MPS therapy is indicated in heart&#44; liver&#44; or kidney transplanted patients to prevent acute rejection&#46; No approved dermatologic uses are listed in the product summaries&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">12</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">However&#44; the use of these drugs has been explored in various inflammatory diseases because liver and kidney toxicity is higher with alternative immunosuppressants&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Onset of action&#44; which is slower than in glucocorticoid or ciclosporin treatment&#44; takes at least 1 month and sometimes 3 to 4 months&#46; This therapeutic option&#44; therefore&#44; is for maintenance of effect&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">58</span></a> either by itself or as a corticosteroid-sparing strategy&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Good outcomes have been reported in pyoderma gangrenosum<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">58</span></a> and severe atopic dermatitis with both MMF<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">56</span></a> and MPS<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">59&#44;60</span></a> in both adults and children&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">61</span></a> Positive results have also been reported in pemphigus vulgaris&#44;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">62</span></a> collagenosis&#44;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">63&#44;64</span></a> chronic idiopathic urticaria&#44;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">65</span></a> and lichen planus and sarcoidosis&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">64</span></a> The results in psoriasis have been less positive&#44;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">66</span></a> although one randomized clinical trial found that efficacy was statistically similar to that of methotrexate&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">67</span></a> Evidence generally comes from single case reports or case series&#46; Hardly any high quality randomized clinical trials have been published&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Immunosuppressant doses of these drugs vary in inflammatory diseases&#59; doses of 500<span class="elsevierStyleHsp" style=""></span>mg to 1<span class="elsevierStyleHsp" style=""></span>g of MMF are given every 12<span class="elsevierStyleHsp" style=""></span>hours &#40;or 720<span class="elsevierStyleHsp" style=""></span>mg of MPS every 12 hours&#41;&#46; If a daily dose of 2<span class="elsevierStyleHsp" style=""></span>g of MMF is reached without response&#44; plasma levels of mycophenolic acid should be measured to rule out poor adherence or decide whether to increase the dose if absorption is low&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">68</span></a> Plasma levels vary greatly between patients and&#44; curiously&#44; between diseases&#46; Mycophenolic acid plasma trough level has been shown to be a poor predictor of the effectiveness and safety of MMF therapy&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">A great advantage of MMF over other immunosuppressants is its good tolerance and safety profile&#44; particularly with regard to renal toxicity&#44; hepatotoxicity&#44; and neurotoxicity&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">The most commonly reported adverse effects &#40;in 12&#37;&#8211;36&#37;&#41; involve the digestive system<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">63</span></a> and include diarrhea&#44; nausea&#44; vomiting&#44; abdominal pain&#44; and soft stools&#46; These effects are dose dependent and rarely oblige discontinuance of treatment&#46; Transaminase levels rise in some patients&#44; but no clinical impact or clear hepatotoxicity has been reported&#46; Enteric-coated MPS is better tolerated&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Leukopenia is observed more often than anemia or thrombocytopenia&#44; and again&#44; the relationship is dose dependant&#46; At dosages of 3<span class="elsevierStyleHsp" style=""></span>g&#47;d&#44; this adverse effect develops in 34&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">64</span></a> If neutrophil counts fall below 1300 cells&#47;mL&#44; discontinuance is indicated&#46; Red cell dysplasia has been reported&#44; particularly in transplanted patients&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">68</span></a> These hematologic effects usually improve quickly when the drug is discontinued or the dose is reduced&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Urinary tract symptoms &#40;dysuria&#44; urgency&#44; frequent urination&#44; sterile pyuria&#44; or hematuria&#41; are not unusual&#44; especially at the beginning of treatment&#46; They usually improve after a year&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Conclusions about the risk of infection and neoplasia vary greatly in the literature&#46; Published studies are difficult to compare&#44; given that transplanted patients tend to receive higher doses and take more concurrent immunosuppressants than patients who have inflammatory diseases&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Cyclophosphamide</span><p id="par0255" class="elsevierStylePara elsevierViewall">Cyclophosphamide is an alkylating agent that interferes with DNA replication by attaching an alkyl group to the guanine base&#44;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">69</span></a> causing cell death&#46; The drug targets T cells and&#44; to a lesser degree&#44; B cells&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">70</span></a> The usual oral dosage is 1 to 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#59; the intravenous dosage is 500&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> of body surface every month&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Because this potent drug has adverse effects&#44; it is reserved for particularly severe cases&#46; Dermatologic indications are autoimmune bullous diseases &#40;especially pemphigus vulgaris and pemphigus foliaceous&#41;&#44; autoimmune systemic vasculitis&#59; severe cutaneous lupus erythematosus&#59; cutaneous manifestations of systemic sclerosis&#59; and cutaneous T-cell lymphoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0740"><span class="elsevierStyleSup">71&#44;72</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">A higher cumulative daily dose increases the risk of toxicity in oral administration&#46; Therefore&#44; different therapeutic regimens have attempted to minimize that risk&#46; Among the strategies tried are monthly intravenous infusions either alone or combined with low-dose oral therapy&#44; and a single immunoablative high dose without stem-cell rescue&#46; The efficacy of these alternative approaches seems to differ little from that of daily oral doses&#46;<a class="elsevierStyleCrossRefs" href="#bib0735"><span class="elsevierStyleSup">70&#8211;76</span></a> Intravenous pulse therapy&#44; however&#44; leads to a lower cumulative dose and seems to be safer&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">77</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Digestive symptoms such as nausea&#44; vomiting&#44; diarrhea&#44; and stomatitis are common&#46; Nausea is reported more in pulse therapy than oral treatment&#46; Antiemetic prophylaxis is recommended&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Myelosuppression is an acute&#44; dose-dependent adverse effect that usually presents with leukopenia&#46; Monitoring is required to adjust the dose to keep the white blood cell count above 3500 to 4000 cells&#47;mL&#46; If the neutrophil count falls to dangerously low levels&#44; granulocytic-colony-stimulating factors may have to be given&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">77</span></a> Treatment with cotrimoxazole or dapsone is recommended to guard against <span class="elsevierStyleItalic">Pneumocystis jirovecii</span> infection&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">73</span></a> Between 9&#37; and 15&#37; of patients had to be hospitalized for severe herpes zoster infection in some series&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">71</span></a> As in the context of other immunosuppressant therapies&#44; pneumococcus as well as regular influenza vaccinations are indicated&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Hemorrhagic cystitis is a typical side effect of cyclophosphamide therapy&#46; The incidence ranges from 8&#37; to 41&#37;&#44; depending on dose&#44; and oral intake seems to be associated with greater risk than pulse treatments&#46; This complication seems to be caused by urinary secretion of a metabolite &#40;acrolein&#41; that irritates the urothelium&#46; Preventive measures include drinking plenty of liquids&#44; not taking the drug at night&#44; and voiding the bladder before going to bed so that acrolein does not remain in contact with the mucosal tissue all night&#46; Intravenous pulse infusion should be accompanied by intense fluid therapy to force diuresis&#46; Adjuvant treatment with sodium 2-mercaptoethane sulfonate &#40;Mesna&#41;&#44; which binds to and deactivates acrolein&#44; is also an option&#46; This drug is given immediately after and again 4 and 8<span class="elsevierStyleHsp" style=""></span>hours after cyclophosphamide&#44; and each infusion should contain a dose that is 20&#37; of the cyclophosphamide dose&#46; In other words&#44; after a dose of 1000<span class="elsevierStyleHsp" style=""></span>mg of cyclophosphamide&#44; the patient should receive 3 doses containing 200<span class="elsevierStyleHsp" style=""></span>mg of Mesna each&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The other adverse effects of cyclophosphamide involve gonadal toxicity&#46; Oral intake in particular seems to lead to premature ovarian failure&#44; azoospermia&#44; menstrual irregularity&#44; and potentially irreversible infertility&#46; The use of testosterone in men and gonadotropin-releasing hormone analogs in women is a subject of debate&#46; Cyclophosphamide should therefore be avoided in patients of reproductive age&#46; If it must be prescribed&#44; the patient should be referred for reproductive counseling to assess the advisability of cryopreservation&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of Interest</span><p id="par0290" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Pretreatment Tests and Vaccinations"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Practical Aspects of Immunosuppressant Therapy"
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          "identificador" => "sec0020"
          "titulo" => "Methotrexate"
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          "identificador" => "sec0025"
          "titulo" => "Ciclosporin"
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          "identificador" => "sec0030"
          "titulo" => "Azathioprine"
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          "identificador" => "sec0035"
          "titulo" => "Mycophenolate Mofetil and Mycophenolate Sodium Salt"
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          "titulo" => "Cyclophosphamide"
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        12 => array:2 [
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          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2016-12-18"
    "fechaAceptado" => "2017-05-14"
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            0 => "Methotrexate"
            1 => "Ciclosporin"
            2 => "Cyclophosphamide"
            3 => "Azathioprine"
            4 => "Mycophenolate"
            5 => "Immunosuppression"
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            0 => "Metotrexato"
            1 => "Ciclosporina"
            2 => "Ciclofosfamida"
            3 => "Azatioprina"
            4 => "Micofenolato"
            5 => "Inmunosupresi&#243;n"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The treatment of inflammatory and autoimmune diseases is challenging because of their frequency and complexity&#46; Treatment of these diseases is based on the suppression of the patient&#39;s immune system using corticosteroids&#44; corticosteroid-sparing immunosuppressive agents&#44; and biologic drugs&#44; making an understanding of the management of immunosuppressive therapy essential&#46; Before an immunosuppressive agent is prescribed&#44; a study must be carried out to identify contraindications&#44; detect latent infections&#44; and determine the most appropriate dose&#46; During treatment&#44; regular monitoring is required to detect adverse effects&#46; The clinician must be familiar with the time lag between start of treatment and onset of the immunosuppressive effect as well as the maximum recommended duration of treatment and cumulative dose for each drug&#46; As dermatologists we are accustomed to using these immunosuppressive agents&#44; but we should have a good knowledge of the guidelines for their use and the monitoring required in each case if we are to reduce variability and avoid potentially serious adverse effects&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las enfermedades inflamatorias y autoinmunes constituyen un desaf&#237;o terap&#233;utico por frecuencia y complejidad&#46; Su tratamiento se basa en la inmunosupresi&#243;n del paciente con glucocorticoides&#44; inmunosupresores ahorradores de corticoides y f&#225;rmacos biol&#243;gicos&#44; siendo imprescindible por tanto conocer su manejo&#46; Cuando se va a pautar un inmunosupresor es necesario realizar un estudio previo para detectar contraindicaciones&#44; infecciones latentes o determinar la dosis m&#225;s adecuada del f&#225;rmaco&#46; Durante el tratamiento se deben realizar controles peri&#243;dicos para detectar efectos secundarios&#46; Cada f&#225;rmaco tiene un tiempo de inicio de acci&#243;n que es preciso conocer&#44; as&#237; como una duraci&#243;n o dosis acumulada m&#225;xima recomendada&#46; Los dermat&#243;logos estamos habituados al uso estos f&#225;rmacos inmunosupresores&#44; pero es necesario tener claras las pautas y los controles necesarios con cada uno&#44; para disminuir la variabilidad y evitar efectos adversos potencialmente graves&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Leis-Dosil V&#44; Prats-Caelles I&#46; Practical Management of Immunosuppressants in Dermatology&#46; Actas Dermosifiliogr&#46; 2018&#59;109&#58;24&#8211;34&#46;</p>"
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ACTH&#44; adrenocorticotropic hormone&#59; GFR&#44; glomerular filtration rate&#59; HBV&#44; hepatitis B virus&#59; HCV&#44; hepatitis C virus&#59; HIV&#44; human immunodeficiency virus&#59; P3NP&#44; procollagen type III N-terminal peptide&#59; TPMT&#44; thiopurine methyltransferase&#46;</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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ciclosporin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Azathioprine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mycophenolate Mofetil and Mycophenolate Sodium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cyclophosphamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top">Complete blood count&#44; including differential white blood cell counts<br>Biochemistry&#44; including glucose&#44; ion concentrations&#44; kidney function&#44; liver function &#40;transaminase&#44; alkaline phosphatase&#44; bilirubin&#44; albumin&#41;&#44; lipids&#44; uric acid<br>Serology for HBV&#44; HBC&#44; and HIV<br>Full vaccination coverage<br>Tuberculosis screening &#40;Mantoux test or quantitative interferon gamma release assay&#41;<br>Pregnancy test in women of childbearing age<br></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindicated if total bilirubin concentration is &#62;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<br>Urinalysis<br>Chest x-ray<br>P3NP level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Estimated GFR to dermine renal function and adjust dosage&#46;<br>Blood pressure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TPMT level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chest x-ray &#40;consider&#41;<br>Urinalysis&#46;<br>Rule out adrenal insufficiency &#40;baseline cortisol and ACTH levels&#44; stimulation test to measure cortisol before and after injection of 250<span class="elsevierStyleHsp" style=""></span>&#956;g of ACTH&#41;&#46;<br>Spermogram and sperm banking prior to treatment&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Complementary Tests to Order Before Starting Immunosuppressant Therapy&#46;</p>"
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      1 => array:8 [
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        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; IV&#44; intravenous&#59; TPMT&#44; thiopurine methyltransferase&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Source&#58; Summaries of product characteristics posted by the Spanish Agency for Medicines and Health Products&#46; Available from https&#58;&#47;&#47;www&#46;aemps&#46;gob&#46;es&#47;cima&#47;fichasTecnicas&#46;do&#63;metodo<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>detalleForm</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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ciclosporin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Azathioprine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mycophenolate Mofetil and Mycophenolate Sodium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cyclophosphamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dermatologic indications in the summary of product characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Psoriasis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Psoriasis&#46;<br>Atopic dermatitis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Systemic lupus erythematosus&#46;<br>Dermatomyositis&#46;<br>Pemphigus vulgaris&#46;<br>Pyoderma gangrenosum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8220;Life-threatening&#8221; autoimmune diseases&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommended dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">From 5 to a maximum of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5&#8211;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d &#40;adjust for TPMT level&#41;&#46;<br>Maximum dosage 200<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mycophenolate mofetil&#58; 1&#8211;2<span class="elsevierStyleHsp" style=""></span>g&#47;d in 2 doses&#46;<br>Mycophenolate sodium&#58; 1080&#8211;1440<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#58; 1&#8211;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#59; maximum&#44; 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46;<br>IV&#58; 500&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> of body surface per month&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Onset of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Slow&#44; 4&#8211;8<span class="elsevierStyleHsp" style=""></span>wk&#46; Wait 12<span class="elsevierStyleHsp" style=""></span>wk before declaring treatment failure&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rapid&#44; 2&#8211;4<span class="elsevierStyleHsp" style=""></span>wk&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May take months&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Most responders improve in 4<span class="elsevierStyleHsp" style=""></span>wk&#59; some need 3<span class="elsevierStyleHsp" style=""></span>mo&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rapid&#44; from 2 to 16<span class="elsevierStyleHsp" style=""></span>wk&#44; around 5<span class="elsevierStyleHsp" style=""></span>wk on average&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Maximum duration of treatment recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Assess liver toxicity at cumulative doses of 1500<span class="elsevierStyleHsp" style=""></span>mg&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to course of disease&#46; Carcinogenic risk after<span class="elsevierStyleHsp" style=""></span>10 y&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">According to tolerance and response&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Significant cumulative toxicity&#44; but can be maintained&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Basic Features of Immunosuppressants to Know When Selecting a Therapy&#46;</p>"
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        "etiqueta" => "Table 3"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; MCV&#44; mean corpuscular volume&#59; NSAID&#44; nonsteroidal anti-inflammatory drug&#59; PIIINP&#44; procollagen type III N-terminal peptide&#46;</p>"
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              "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5<span class="elsevierStyleHsp" style=""></span>mg tablets&#46;<br>Prefilled syringes &#40;7&#46;5&#44; 10&#44; 15&#44; 20&#44; 25&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Initial dosing&#58; 7&#46;5&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#46; Schedule a specific day of the week to avoid confusion&#46;<br>Gradually increase the dose as needed&#46; Avoid exceeding 20<span class="elsevierStyleHsp" style=""></span>mg&#47;wk&#46;<br>Supplement with folic acid&#44; 5&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;wk taken 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h after the methotrexate dose&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete blood count&#44; including ion concentration and kidney and liver function profiles&#46; Increase the dose after 1 wk and then after 2&#44; 4&#44; 6&#44; 10&#44; 14&#44; and 18<span class="elsevierStyleHsp" style=""></span>wk&#59; then after 3 mo&#46;<br>PIIINP every 3 mo&#46;<br>Elastography &#40;FibroScan&#41; if an abnormal PIIINP concentration is found more than twice&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pregnancy &#40;and men should not father a child until 3 mo after interrupting treatment&#41;&#46; Severe liver disease&#46; Marked cytopenia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Live or attenuated virus vaccines&#44; cotrimoxazole&#44; phenytoin&#44; ciclosporin&#44; azathioprine&#44; NSAIDs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pregnancy&#46; Significant&#44; sustained increase in PIINP concentration&#46; Sustained MCV increase that does not resolve with folic acid&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Practical Aspects of Treatment With Methotrexate&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ACE&#44; angiotensin converting enzyme&#46;</p>"
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              "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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Capsules of 25&#44; 50&#44; and 100<span class="elsevierStyleHsp" style=""></span>mg&#46;<br>Oral solution&#44; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Initial dosing&#58; 2&#46;5&#8211;3&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d &#40;calculated based on ideal weight&#44; not actual weight&#44; to avoid overdosing&#41;&#46;<br>Maintenance at the lowest effective dose&#46;<br>Do not exceed 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Blood pressure weekly&#44; always under the same conditions&#46; The patient should record readings and bring them to medical visits&#46;<br>Laboratory tests&#58; Complete blood count&#44; including ion concentrations&#44; kidney and liver function profiles&#44; uric acid level&#44; and urinalysis&#46; Repeat every 2<span class="elsevierStyleHsp" style=""></span>wk for the first 3<span class="elsevierStyleHsp" style=""></span>mo&#44; then monthly&#46;<br>Drug levels can be measured if interactions or poor adherence is suspected&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Active infections&#46; Neoplasms &#40;rule out basal cell carcinoma&#41;&#46; Uncontrolled arterial hypertension&#46;<br>No not use phototherapy&#44; due to increased risk of tumors&#46;<br>Kidney failure &#40;monitor renal function&#41;&#46;<br>Liver failure&#44; cirrhosis &#40;avoid ciclosporin or use low doses&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Numerous interactions with drugs metabolized by cytochrome P450 and CYP34A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">After 1<span class="elsevierStyleHsp" style=""></span>y of therapy &#40;recommended&#41;&#46;<br>Hypertension detected on 2 measurements after which the dosage is lowered 25&#37;&#59; if there is no improvement&#44; add an antihypertensive medication &#40;a dihydropyridine calcium channel blocker&#44; an ACE inhibitor&#44; or an angiotensin-II receptor blocker&#41;&#59; if no improvement&#44; discontinue ciclosporin&#46;<br>Kidney toxicity&#58; if creatinine clearance is impaired according to 2 measurements within 2 wk&#44; lower the dose 25&#37;&#59; if there is improvement&#44; maintain ciclosporin at the lower dose&#59; if no improvement&#44; discontinue&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Practical Aspects of Treatment With Ciclosporin&#46;</p>"
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        "etiqueta" => "Table 5"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ACE&#44; angiotensin converting enzyme&#59; MCV&#44; mean corpuscular volume&#59; TPMT&#44; thiopurine methyltransferase&#46;</p>"
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                  <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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tablets of 50<span class="elsevierStyleHsp" style=""></span>mg&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;5&#8211;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46; Adjust for TPMT activity&#46;<br>Start at a low dose and increase according to tolerance and response&#46;<br>If TPMT testing is unavailable&#44; start with a low dose &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; and gradually increase with strict follow-up &#40;complete blood count&#41;&#46; If MCV increases less than 3<span class="elsevierStyleHsp" style=""></span>fL in 3 mo&#44; the dosage can be increased 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#46; If MCV increases &#62;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>fL&#44; lower the dosage 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d and repeat testing&#44; including for folic acid and vitamin B<span class="elsevierStyleInf">12</span>&#46;<br>Divide the daily dose in 2 fractions to improve gastrointestinal tolerance&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete blood count&#44; kidney function&#44; liver function at 1&#44; 2&#44; 3&#44; 4&#44; 6&#44; 8&#44; 12&#44; 16&#44; and 20 wk&#46; Then&#44; every 3 mo&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Allergy to azathioprine or 6-mercaptopurine&#46; Neoplasms &#40;current&#41;&#46; TPMT absent or &#60;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mycophenolate mofatil&#44; mycophenolate sodium&#46; Live or attenuated virus vaccines&#46; Allopurinol&#46; Sulfasalazine&#46; Cotrimoxazole&#46; ACE inhibitors&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breastfeeding&#46; Assess risks-benefits during pregnancy&#46;<br>Hypersensitivity reaction&#46;<br>Pancreatitis&#46; Hepatotoxicity&#46;<br>Myelotoxicity&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Practical Aspects of Treatment With Azathioprine&#46;</p>"
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        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; MMF&#44; mycophenolate mofetil&#59; MPS&#44; mycophenolate sodium&#46;</p>"
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                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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPS&#58; enteric-coated tablets of 180 and 360<span class="elsevierStyleHsp" style=""></span>mg&#46;<br>MMF&#58; capsules of 250<span class="elsevierStyleHsp" style=""></span>mg&#44; coated tablets of 500<span class="elsevierStyleHsp" style=""></span>mg&#44; powder for oral suspension of 1<span class="elsevierStyleHsp" style=""></span>g&#47;5<span class="elsevierStyleHsp" style=""></span>mL&#44; vials of 500<span class="elsevierStyleHsp" style=""></span>mg&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPS&#58; 720<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#46;<br>MMF&#58; start with 250&#8211;500<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h and increase every wk until a dosage of 1<span class="elsevierStyleHsp" style=""></span>g&#47;12<span class="elsevierStyleHsp" style=""></span>h can be maintained&#46; Never administer a bolus dose intravenously&#46;<br>Capsules and tablets should be swallowed whole with a glass of water&#46;<br>MMF can be taken with or without food&#46; MPS can also be ingested with or without food&#44; but once a habit is started it should be continued&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete blood count every 2<span class="elsevierStyleHsp" style=""></span>wk in the first month&#44; then monthly for 3<span class="elsevierStyleHsp" style=""></span>mo&#44; then every 2<span class="elsevierStyleHsp" style=""></span>mo&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pregnancy&#44; breastfeeding&#44; drug allergy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Azathioprine&#44; ciclosporin&#44; live virus and attenuated virus vaccines&#44; aciclovir&#44; colestyramine&#44; tacrolimus&#44; rifampicin&#44; antacids&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe leukopenia &#40;&#60;1300<span class="elsevierStyleHsp" style=""></span>cells&#47;mL&#41;&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">Practical Aspects of Treatment With Mycophenolate Mofetil and Mycophenolate Sodium&#46;</p>"
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        "etiqueta" => "Table 7"
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                  <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="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pharmaceutical forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tablets of 50<span class="elsevierStyleHsp" style=""></span>mg&#46;<br>Vials of 200 and 1000<span class="elsevierStyleHsp" style=""></span>mg in solution&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&#58; 50&#8211;100<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#59; can be increased to 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d in severe cases&#46; The tablet must be taken whole&#44; neither chewed nor crushed&#46; To minimize side effects&#44; take in single doses in the morning and drink plenty of liquids &#40;3<span class="elsevierStyleHsp" style=""></span>L&#47;d&#41;&#46; Empty bladder before going to sleep&#46; Take antiemetics if necessary&#46;<br>Intravenous pulse therapy&#58; starting dose&#44; 500<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#59; then 750<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#59; then&#44; if tolerated&#44; 1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#46; Administer intravenous fluids in abundance&#46; Prescribe antiemetics&#44; possibly before cyclophosphamide&#46; Evaluate possible use of intravenous infusion&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monitoring during treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Oral therapy</span><br>Complete blood count every 7&#8211;14<span class="elsevierStyleHsp" style=""></span>d for 1<span class="elsevierStyleHsp" style=""></span>mo on initiating treatment and after any dosage changes&#46; Then every 1&#8211;3<span class="elsevierStyleHsp" style=""></span>mo&#46; Adjust dosage to maintain white blood cell count &#62;<span class="elsevierStyleHsp" style=""></span>4000<span class="elsevierStyleHsp" style=""></span>cells&#47;mL&#46;<br>Urinalysis every 1&#8211;3<span class="elsevierStyleHsp" style=""></span>mo&#46;<br>Urine cytology 1&#8211;2<span class="elsevierStyleHsp" style=""></span>times&#47;y&#46;<br>Cytoscopy if blood in urine or abnormal cytology findings&#46;<br>Liver workup every 3<span class="elsevierStyleHsp" style=""></span>mo&#46;<br>Pregnancy test&#46;<br><span class="elsevierStyleItalic">Intravenous pulse therapy&#58;</span><br>Complete blood count immediately after an infusion and 10&#8211;14<span class="elsevierStyleHsp" style=""></span>d later&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Contraindications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absolute&#58; Pregnancy and breastfeeding&#44; drug allergy&#44; myelosuppression&#44; history of bladder cancer&#46;<br>Relative&#58; active infection&#44; liver or kidney failure&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Concurrent drugs to avoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Succinylcholine&#44; anticholinergic agents&#44; allopurinol&#44; busulfan&#44; chlorpromazine&#44; ciprofloxacin&#44; fluconazole&#44; thiotepa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indications for discontinuing therapy or adjusting the dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bladder cancer&#44; acute cardiotoxicity&#46;&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="spar0085" class="elsevierStyleSimplePara elsevierViewall">Practical Aspects of Treatment With Cyclophosphamide&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:77 [
            0 => array:3 [
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              "etiqueta" => "1"
              "referencia" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "M&#46;E&#46; Cotes"
                            1 => "R&#46;A&#46; Swerlick"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/dth.12026"
                      "Revista" => array:6 [
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                        "fecha" => "2013"
                        "volumen" => "26"
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            1 => array:3 [
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              "etiqueta" => "2"
              "referencia" => array:1 [
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            ]
            2 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vaccination in patients with primary immune deficiency&#44; secondary immune deficiency and autoimmunity with immune regulatory abnormalities"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;M&#46; Eibl"
                            1 => "H&#46;M&#46; Wolf"
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                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2217/IMT.15.74"
                      "Revista" => array:6 [
                        "tituloSerie" => "Immunotherapy"
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                        "volumen" => "7"
                        "paginaInicial" => "1273"
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            ]
            3 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Executive Summary&#58; 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;G&#46; Rubin"
                            1 => "M&#46;J&#46; Levin"
                            2 => "P&#46; Ljungman"
                            3 => "E&#46;G&#46; Davies"
                            4 => "R&#46; Avery"
                            5 => "M&#46; Tomblyn"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cid/cit816"
                      "Revista" => array:6 [
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                        "fecha" => "2014"
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                        "link" => array:1 [
                          0 => array:2 [
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            4 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "General recommendations on immunization&#58; Recommendations of the advisory Committee on Immunization Practices &#40;ACIP&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;T&#46; Kroger"
                            1 => "C&#46;V&#46; Sumaya"
                            2 => "L&#46;K&#46; Pickering"
                            3 => "W&#46;L&#46; Atkinson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Pediatrics"
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                        "volumen" => "119"
                        "paginaInicial" => "1008"
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                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Revisi&#243;n de las recomendaciones de vacunaci&#243;n frente a varicela en grupos de riesgo&#46; Ponencia de Programas y Registro de Vacunaciones"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Limia-S&#225;nchez"
                            1 => "S&#46; Ca&#241;ellas-Llabr&#233;s"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:3 [
                        "fecha" => "2015"
                        "editorial" => "Ministerio de Sanidad&#44; Servicios Sociales e Igualdad"
                        "editorialLocalizacion" => "Madrid"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Recomendaciones de Programas de Vacunaciones&#46; Vacunaci&#243;n frente a neumococo en grupos de riesgo&#46; 2015 &#91;cited 2016 Dec 11&#93;&#46; Available from&#58; <a href="https://www.msssi.gob.es/eu/profesionales/saludPublica/prevPromocion/vacunaciones/docs/Neumococo_Gruposriesgo.pdf">https&#58;&#47;&#47;www&#46;msssi&#46;gob&#46;es&#47;eu&#47;profesionales&#47;saludPublica&#47;prevPromocion&#47;vacunaciones&#47;docs&#47;Neumococo&#95;Gruposriesgo&#46;pdf</a>"
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "8"
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2017.11.004

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2019 August	4	0	4
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2019 April	2	0	2
2019 March	4	0	4
2019 January	2	0	2
2018 December	5	0	5
2018 October	3	0	3
2018 September	4	0	4
2018 May	1	0	1
2018 February	71	47	118
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