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Azathioprine: its uses in dermatology
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"Chavez-Alvarez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Maira" "apellidos" => "Herz-Ruelas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Alejandra" "apellidos" => "Villarreal-Martinez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Jorge" "apellidos" => "Ocampo-Candiani" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Rubicela" "apellidos" => "Garza-Garza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:4 [ "nombre" => "Minerva" "apellidos" => "Gomez-Flores" "email" => array:1 [ 0 => "minervagomezmx@yahoo.com.mx" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Dermatology, University Hospital “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Nuevo León, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Private Dermatology Practice, San Pedro Garza Garcia, Nuevo Leon, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 957 "Ancho" => 2167 "Tamanyo" => 105386 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Azathioprine metabolism.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Azathioprine was first used to prevent graft-versus-host disease. Today it is widely used as an immunomodulator, immunosuppressant, and a steroid-sparing agent.</p><p id="par0010" class="elsevierStylePara elsevierViewall">It is a pro-drug that is rapidly converted to 6-mercaptopurine (6-MP) by means of the purine metabolism pathway, and its therapeutic effects are derived from its purine anti-metabolism.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> As a purine analogue, it inhibits DNA production and exerts effects on cells with a high proliferation rate (<span class="elsevierStyleItalic">i.e</span>., T and B lymphocytes).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0021" class="elsevierStylePara elsevierViewall">It is an approved to prevent graft <span class="elsevierStyleItalic">vs</span>. host disease in organ transplant recipients, severe rheumatoid arthritis, systemic lupus erythematosus, and atopic dermatitis.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> In dermatology, it is used off-label for other several conditions.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Metabolism and pharmacodynamics</span><p id="par0020" class="elsevierStylePara elsevierViewall">It is synthesized from 6-MP and an imidazolic ring in the sulfur atom which stabilizes the molecule and avoids immediate catabolism.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This purine antimetabolite inhibits the S phase of the cell cycle. The metabolism of endogenous purines produces 6-MP.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Three metabolic pathways exist within liver and erythrocytes: xanthine oxidase, thiopurine methyltransferase (TPMT), and hypoxanthine phosphoribosyltransferase. The latter is responsible for the drug's activity, while the first two are the main catabolic pathways and produce inactive metabolites like thiouric acid (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">For 6-MP to affect the synthesis of nucleic acids, it needs to be converted into thioinosinic acid.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This nucleotide inhibits mitosis, coenzyme formation, neutrophils, and monocytes, as well as suppressing the synthesis of prostaglandins by means of cyclooxygenase (COX).<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> It has a selective activity for T over B lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Between 70% and 80% of the drug is absorbed within the gastrointestinal tract and it reaches peak serum levels two hours after ingestion.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,9</span></a> It does not cross the blood-brain barrier.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Dose</span><p id="par0030" class="elsevierStylePara elsevierViewall">Adults require 1–3<span class="elsevierStyleHsp" style=""></span>mg/kg/day and 1–4<span class="elsevierStyleHsp" style=""></span>mg/kg/day is the pediatric dose.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,5</span></a> Therapeutic effects are seen one to two months after starting the drug. Dose adjustments must be made according to each patients’ response.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,8</span></a> Administration with meals in divided doses is suggested.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Maintenance can extend to 93 months.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Precautions before treatment</span><p id="par0035" class="elsevierStylePara elsevierViewall">It is advisable to thoroughly explain information regarding this medication to the patient. Those unable to be closely monitored are not eligible for treatment.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Request:</span><p id="par0040" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1.</span><p id="par0045" class="elsevierStylePara elsevierViewall">Antigens for hepatitis B and C, enzyme-linked immunosorbent assay (ELISA) for HIV.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2.</span><p id="par0050" class="elsevierStylePara elsevierViewall">Human chorionic gonadotropin (if indicated).</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3.</span><p id="par0055" class="elsevierStylePara elsevierViewall">Complete blood cell count, blood chemistry, and liver function tests, before treatment and twice a month for the first three months. Finalizing this period, a bimonthly follow-up is required.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4.</span><p id="par0060" class="elsevierStylePara elsevierViewall">Annual tuberculosis screening.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></li></ul></p><p id="par0065" class="elsevierStylePara elsevierViewall">Hepatic or renal malfunction mandates lower doses. If suspension of the medication is required, adverse effects will gradually diminish because of persistence of the active metabolite.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Patients without a history of varicella zoster infection receiving treatment and recent close contact with the virus should be promptly treated with immunoglobulin. Administration of live virus vaccines for the patient and relatives is prohibited due to the existing risk of transmission. Family members should receive inactivated virus vaccines.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Children over 6 months of age and those not responding to safer medications are eligible. Treatment for short periods may induce prolonged remissions. Dose tapering must be done in six months up to one year.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Fertility is not adversely affected; however, there is scarce evidence.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It is advisable to avoid pregnancy and use contraception during treatment.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Adverse events include a preterm or underweight child.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a> Azathioprine passes the placental barrier and the fetal liver lacks enzymes required for its conversion into active metabolites.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Hematological toxicity and sporadic anomalies are also described. There is no established pattern of congenital malformations (which may include atrial or ventricular septal defects). The malformation rate varies from 3% to 9% and includes myelomeningocele, microcephaly, preaxial polydactyly, thymic atrophy, and adrenal hypoplasia and/or hypospadias.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">It is a category D drug in pregnancy (acceptable benefits but risks to fetuses). Its use should be reserved for life threatening diseases.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Patients should receive half the dose in the 32<span class="elsevierStyleSup">nd</span> week of gestation if their leukocyte count is less than one standard deviation below the mean. This helps prevent leukopenia and/or thrombocytopenia in the baby.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> A study involving pregnant women receiving azathioprine for eight weeks in the first trimester resulted in scarce evidence linking it to congenital malformations, low birth weight, and/or prematurity.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In males, no anomalies in seminal fluid three months after initiation of treatment were described in patients with inflammatory bowel disease (IBD).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Breastfeeding is not advisable during treatment due to the risk of tumorigenesis and increased infections in infants.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> However, a three-year follow-up study in children of patients with IBD receiving azathioprine found no significant differences in the rate of infections compared with children of healthy mothers.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Most of the 6-MP is excreted in milk four hours following ingestion, though the quantity ingested by infants is not considered significant.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">TPMT deficiency</span><p id="par0100" class="elsevierStylePara elsevierViewall">TPMT is an inducible enzyme and its levels vary with time.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Initial measurement of this enzyme is required. Otherwise, there is a risk of adverse effects or treatment at subtherapeutic doses.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Myelosuppression (neutropenia and pancytopenia) may be present with regular doses. An unidentified pancytopenia may become lethal.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Ten percent of individuals have low TPMT activity, which generates thiopurine toxicity.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Resultant accumulation of thioguanine nucleotides affect bone marrow.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Those with no TPMT activity should not be prescribed azathioprine.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A greater activity of TPMT confers less risk to induce a myelosuppressive response (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Applications in dermatology</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pemphigus vulgaris</span><p id="par0105" class="elsevierStylePara elsevierViewall">Used as first-line steroid sparing agent. It offers better results as compared to mycophenolate mofetil (MMF).<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,18</span></a> Another drug, cyclophosphamide, has a faster onset of action; however, treatment effectiveness is comparable at six months.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> When combined with prednisone, final outcomes are better, with benefits such as a greater number of patients in remission and less adverse effects (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Bullous pemphigoid</span><p id="par0110" class="elsevierStylePara elsevierViewall">Starting a steroid-sparing agent since the initiation of treatment is advisable. Time of onset of the therapeutic effects for azathioprine varies from one week to seven months. At a four-year follow-up, 44% of patients achieve remission of the disease.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It halts disease progression and promotes re-epithelialization as soon as eight weeks of starting treatment.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> MMF is less hepatotoxic, but five times as costly. A faster and complete cure was also demonstrated when compared with MMF (23.8 <span class="elsevierStyleItalic">vs</span>. 42 days).<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> However, no differences in disease control have been identified with prednisolone alone, azathioprine and prednisolone, prednisolone with plasmapheresis, or prednisolone with azathioprine or MMF.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Chronic actinic dermatitis</span><p id="par0115" class="elsevierStylePara elsevierViewall">It induces 57% to 92% of improvement in patients when compared with placebo. Dosage varies between 1–2.5<span class="elsevierStyleHsp" style=""></span>mg/kg. Adverse effects observed in patients treated with azathioprine for this condition include three deaths, 12–15 months after stopping treatment (secondary to cerebrovascular disease, lung disease, and another due to heart disease).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It has demonstrated effectiveness in refractory disease. Drug interactions need to be reviewed since these patients have polypharmacy, which is why it is preferred over cyclosporine.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Psoriasis</span><p id="par0120" class="elsevierStylePara elsevierViewall">It may be indicated for patients with refractory disease.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It can be used in conjunction with biologicals (not recommended as monotherapy).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Combined with infliximab (5<span class="elsevierStyleHsp" style=""></span>mg/kg), it induces improvement.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Intermittent pulse monotherapy may be effective giving 500<span class="elsevierStyleHsp" style=""></span>mg doses administered for three consecutive days each month, and 100<span class="elsevierStyleHsp" style=""></span>mg daily continuously for 12 to 24 months. Remission may be achieved for more than five years in some patients.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Atopic dermatitis</span><p id="par0125" class="elsevierStylePara elsevierViewall">Information is scarce; however, it has been shown to be as effective as methotrexate.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,27,28</span></a> It is recommended for recalcitrant variants in pediatric patients or when there is a significant psychosocial impact on the patient and their family.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">It can be used in combination and as a steroid-sparing agent.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It reduces the SAS-SAD scale by 26% when compared with placebo (3%) after three months of treatment.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> When used for 12 weeks, the activity of the dermatosis was reduced by 37% <span class="elsevierStyleItalic">vs.</span> 20% in the placebo group.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> A 27% improvement in the severity scoring of atopic dermatitis (SSAD) was also demonstrated after six months.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cutaneous vasculitis</span><p id="par0135" class="elsevierStylePara elsevierViewall">It is effective when combined with prednisolone for purpura, ulcers, nail fold microinfarcts, and/or peripheral necrosis at 2<span class="elsevierStyleHsp" style=""></span>mg/kg. There is significant improvement in vasculitis after 18 months of treatment, and 88% of patients achieved complete remission. Side effects included septic arthritis, epidural abscess, gastrointestinal effects, and an isolated death from renal failure (due to severe vasculitis).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">For leukocytoclastic vasculitis it is recommended as a second-line therapy in steroid resistant Henoch–Schoenlein purpura, but it has been used successfully and has improved the course of nephritis.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">In ANCA vasculitis, azathioprine <span class="elsevierStyleItalic">vs.</span> rituximab were compared to maintain remission of the disease. More patients remained in remission at 28 months with rituximab <span class="elsevierStyleItalic">vs</span>. azathioprine.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Intractable pruritus</span><p id="par0150" class="elsevierStylePara elsevierViewall">In a retrospective study of patients with chronic pruritus (85% of patients with symptoms for 12 months or more) who transiently responded to a course of systemic steroids but were refractory to other treatments, azathioprine was initiated, with a mean starting dose of 137.5<span class="elsevierStyleHsp" style=""></span>mg/day. The pruritus scale was modified from a 9 to a 1 or 2.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Connective tissue diseases (lupus)</span><p id="par0155" class="elsevierStylePara elsevierViewall">Useful in refractory subacute cutaneous lupus erythematosus, generalized discoid lupus, and the erosive palmoplantar type, demonstrating a complete or partial improvement. Rowell's syndrome shows good therapeutic response when combined with prednisolone.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">For systemic lupus erythematosus with cutaneous manifestations and nephritis, 1<span class="elsevierStyleHsp" style=""></span>mg/kg daily can be added to cyclophosphamide (0.05 to 1.00<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> body surface per month for six months).<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Dermatomyositis</span><p id="par0165" class="elsevierStylePara elsevierViewall">In retrospective case series, it has been shown to be effective. It is considered equally effective when compared to methotrexate. If patients have an inadequate response to these medications, combined treatment offers good results in refractory disease.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> It is also recommended to prevent relapses for long periods (one to three years).<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Other uses in dermatology</span><p id="par0170" class="elsevierStylePara elsevierViewall">In an open-label pilot, uncontrolled study for moderate and severe alopecia areata a 2<span class="elsevierStyleHsp" style=""></span>mg/kg dose provided remarkable improvement.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In a prospective study with 14 patients diagnosed with the universalis variant, recalcitrant to other systemic and topical therapies, 43% had a therapeutic response with a mean dose of 142<span class="elsevierStyleHsp" style=""></span>mg daily and a mean duration of therapy of ten months. Total regrowth was seen in 63% and 29% maintained response at 18 months of follow-up.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">One case with eosinophilic fasciitis and generalized morphea was treated with 200<span class="elsevierStyleHsp" style=""></span>mg/day for two months with subsequent tapering to 100<span class="elsevierStyleHsp" style=""></span>mg/day. Remission was maintained 18 months after treatment.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In sarcoidosis, it has demonstrated improvement in some cases; however, compared with methotrexate, azathioprine exhibited a similar response but greater toxicity.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Bullous pemphigoid and psoriasis can co-exist, and cases have been successfully managed with azathioprine (50–150<span class="elsevierStyleHsp" style=""></span>mg/day). It prevents reactivation of psoriasis when interrupting steroids.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> In conjunction with acitretin it is used for erythrodermic psoriasis and bullous pemphigoid.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Adverse effects/toxicity</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Short term</span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Nausea</span><p id="par0190" class="elsevierStylePara elsevierViewall">This is the most frequent dose dependent adverse effect. It arises at the beginning of treatment and improves even without altering the dose. To avoid it, doses are started at their lowest range; <2.5<span class="elsevierStyleHsp" style=""></span>mg/kg reduces abandonment rate by 20%.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The dose can be split and taken with meals.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Hypersensitivity to azathioprine</span><p id="par0195" class="elsevierStylePara elsevierViewall">This idiosyncratic reaction is immunologically mediated. It presents within a few weeks of starting the medication. Identification is essential since it may be misinterpreted as a sign of infection. Patients may have fever, myalgia, arthralgia, nausea, hepatitis, interstitial nephritis, renal failure, and pneumonitis.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Cutaneous signs include erythema nodosum, Sweet's syndrome, small vessel vasculitis, acute generalized pustulosis, and other non-specific dermatoses. Hypotension and shock may develop in severe cases.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">It is possibly underdiagnosed, and atopic eczema patients are the most likely to develop it. Cutaneous signs and symptoms resolve five days after interrupting the drug.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,44</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Medium term</span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Myelotoxicity</span><p id="par0205" class="elsevierStylePara elsevierViewall">This is characterized by leukopenia, thrombocytopenia, anemia, and/or pancytopenia.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Neutropenia is dose dependent. This serious side effect may happen more often than presumed. Approximately 19% of patients develop neutropenia.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Clinical infection, pharyngeal ulceration, ecchymosis, and/or bleeding can lead to its identification. Monitoring is required if there is a decrease in platelet and white blood cell count within the normal lower limit. If lymphocytes decrease <0.50<span class="elsevierStyleHsp" style=""></span>k/uL, it is advisable to reduce the dose. If alterations in platelet count show <50<span class="elsevierStyleHsp" style=""></span>k/uL and/or neutrophils are <1.0<span class="elsevierStyleHsp" style=""></span>k/uL, a hematology consultation is recommended.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Infections</span><p id="par0215" class="elsevierStylePara elsevierViewall">There is increased susceptibility to infections due to lymphopenia even without neutropenia. Latent tuberculosis patients are at risk of reactivation when starting treatment.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Hepatotoxicity</span><p id="par0220" class="elsevierStylePara elsevierViewall">Reversible portal fibrosis and/or minimal cholestasis may develop.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Mild changes in liver function tests without serious clinical implications are frequent. There are two types of hepatotoxicity for azathioprine: idiosyncratic acute liver injury, with hepatocellular disease (severe transaminase increase) or cholestasis (increase in alkaline phosphatase and bilirubin).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> These resolve by decreasing or withdrawing medication.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,5</span></a> Serious hepatotoxicity is rare.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Long term</span><p id="par0225" class="elsevierStylePara elsevierViewall">There is a risk of cutaneous infections and hematological or cutaneous neoplasms.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> However, when used exclusively for dermatological conditions, this is unlikely since the dosage is lower and time of use is shorter.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conclusion</span><p id="par0230" class="elsevierStylePara elsevierViewall">Azathioprine is a useful medication in patients with complex dermatologic conditions and/or resistant to conventional treatments. It has been approved for diseases like lupus, dermatomyositis, and pemphigus vulgaris. It is essential for the dermatologist to adequately educate the patient who will receive the medication for its adverse effects. Physicians should be aware that these undesired effects improve and resolve when azathioprine is decreased or interrupted. It is always recommended to start at the lowest possible dose in order to improve tolerance and to avoid permanent discontinuation of a drug that can be extremely beneficial for the patient.</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Financial support</span><p id="par0235" class="elsevierStylePara elsevierViewall">None declared.</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Authors’ contributions</span><p id="par0240" class="elsevierStylePara elsevierViewall">Sonia Chavez-Alvarez: Statistical analysis; approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; critical review of the literature; critical review of the manuscript.</p><p id="par0245" class="elsevierStylePara elsevierViewall">Maira Herz-Ruelas: Critical review of the literature.</p><p id="par0250" class="elsevierStylePara elsevierViewall">Alejandra Villarreal-Martinez: Design and planning of the study; drafting and editing of the manuscript.</p><p id="par0255" class="elsevierStylePara elsevierViewall">Jorge Ocampo-Candiani: Approval of the final version of the manuscript; effective participation in research orientation.</p><p id="par0260" class="elsevierStylePara elsevierViewall">Rubicela Garza-Garza: Effective participation in research orientation; critical review of the manuscript.</p><p id="par0265" class="elsevierStylePara elsevierViewall">Minerva Gomez-Flores: Design and planning of the study; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicts of interest</span><p id="par0270" class="elsevierStylePara elsevierViewall">None declared.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1418419" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1297628" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Metabolism and pharmacodynamics" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Dose" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Precautions before treatment" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Request:" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "TPMT deficiency" ] ] ] 4 => array:3 [ "identificador" => "sec0035" "titulo" => "Applications in dermatology" "secciones" => array:11 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Pemphigus vulgaris" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Bullous pemphigoid" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Chronic actinic dermatitis" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Psoriasis" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "Atopic dermatitis" ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Cutaneous vasculitis" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Intractable pruritus" ] 7 => array:2 [ "identificador" => "sec0075" "titulo" => "Connective tissue diseases (lupus)" ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Dermatomyositis" ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Other uses in dermatology" ] 10 => array:3 [ "identificador" => "sec0090" "titulo" => "Adverse effects/toxicity" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0095" "titulo" => "Short term" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0100" "titulo" => "Nausea" ] 1 => array:2 [ "identificador" => "sec0105" "titulo" => "Hypersensitivity to azathioprine" ] ] ] 1 => array:3 [ "identificador" => "sec0110" "titulo" => "Medium term" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0115" "titulo" => "Myelotoxicity" ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Infections" ] 2 => array:2 [ "identificador" => "sec0125" "titulo" => "Hepatotoxicity" ] ] ] 2 => array:2 [ "identificador" => "sec0130" "titulo" => "Long term" ] ] ] ] ] 5 => array:2 [ "identificador" => "sec0135" "titulo" => "Conclusion" ] 6 => array:2 [ "identificador" => "sec0140" "titulo" => "Financial support" ] 7 => array:2 [ "identificador" => "sec0145" "titulo" => "Authors’ contributions" ] 8 => array:2 [ "identificador" => "sec0150" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-01-13" "fechaAceptado" => "2020-05-19" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1297628" "palabras" => array:3 [ 0 => "Autoimmunity" 1 => "Azathioprine" 2 => "Pemphigus" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This is a narrative review of azathioprine. This medication is immunomodulatory and immunosuppressive, and it has been used widely through different medical specialties to modify disease. It has been proven useful for several dermatoses and it has encountered success when used as an off-label indication for other dermatologic diseases. Its mechanism of action is described thoroughly, as well as precautions for monitoring adequate levels in patients using it. Dermatologists should also be aware of the possible adverse events it may present. In dermatology it can be used in bullous and autoimmune diseases, and in other conditions, including intractable pruritus, atopic dermatitis, photodermatoses, psoriasis, and others. Azathioprine offers an alternative as a steroid-sparing agent and this review helps dermatologists prescribe it safely to all patients who require it.</p></span>" ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "⋆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">How to cite this article: Chavez-Alvarez S, Herz-Ruelas M, Villareal-Martinez A, Ocampo-Candiani J, Garza-Garza R, Gomez-Flores M. Azathioprine: its uses in dermatology. An Bras Dermatol. 2020. <span class="elsevierStyleInterRef" id="intr0005" href="https://doi.org/10.1016/j.abd.2020.05.003">https://doi.org/10.1016/j.abd.2020.05.003</span></p>" ] 1 => array:2 [ "etiqueta" => "⋆⋆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Study conducted at the University Hospital “Dr. Jose Eleuterio Gonzalez”, Nuevo León, México.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 957 "Ancho" => 2167 "Tamanyo" => 105386 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Azathioprine metabolism.</p>" ] ] 1 => 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" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Adapted from Patel et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TPMT levels \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dosage of azathioprine \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><5 U \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5–13.7 U \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Up to 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.7–19 U \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Up to 1.5<span class="elsevierStyleHsp" style=""></span>mg/kg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>19 U \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Up to 2.5<span class="elsevierStyleHsp" style=""></span>mg/kg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2433431.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Thiopurine methyltransferase (TPMT) levels and azathioprine dosage</p>" ] ] 2 => 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: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=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relative \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Absolute \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Use of allopurinol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 MP hypersensitivity or azathioprine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Previous treatment with cyclophosphamide or chlorambucil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe active infection \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Altered liver function \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral hepatitis, HIV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Altered bone marrow function \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Previous infection by VZV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pancreatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pre-malignancy</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Live virus vaccines \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pregnancy/breastfeeding \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2433430.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Azathioprine contraindications.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:44 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Off-label use of azathioprine in dermatology: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.E. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 29 | 14 | 43 |
| 2024 Outubro | 143 | 74 | 217 |
| 2024 Setembro | 180 | 89 | 269 |
| 2024 Agosto | 163 | 95 | 258 |
| 2024 Julho | 148 | 108 | 256 |
| 2024 Junho | 135 | 88 | 223 |
| 2024 Maio | 96 | 86 | 182 |
| 2024 Abril | 98 | 91 | 189 |
| 2024 Março | 105 | 78 | 183 |
| 2024 Fevereiro | 130 | 74 | 204 |
| 2024 Janeiro | 76 | 42 | 118 |
| 2023 Dezembro | 104 | 57 | 161 |
| 2023 Novembro | 87 | 73 | 160 |
| 2023 Outubro | 69 | 86 | 155 |
| 2023 Setembro | 77 | 77 | 154 |
| 2023 Agosto | 63 | 44 | 107 |
| 2023 Julho | 75 | 48 | 123 |
| 2023 Junho | 66 | 35 | 101 |
| 2023 Maio | 69 | 29 | 98 |
| 2023 Abril | 60 | 22 | 82 |
| 2023 Março | 75 | 49 | 124 |
| 2023 Fevereiro | 51 | 30 | 81 |
| 2023 Janeiro | 52 | 53 | 105 |
| 2022 Dezembro | 56 | 28 | 84 |
| 2022 Novembro | 68 | 55 | 123 |
| 2022 Outubro | 63 | 55 | 118 |
| 2022 Setembro | 46 | 60 | 106 |
| 2022 Agosto | 42 | 48 | 90 |
| 2022 Julho | 44 | 53 | 97 |
| 2022 Junho | 48 | 51 | 99 |
| 2022 Maio | 30 | 51 | 81 |
| 2022 Abril | 45 | 54 | 99 |
| 2022 Março | 35 | 65 | 100 |
| 2022 Fevereiro | 18 | 52 | 70 |
| 2022 Janeiro | 41 | 86 | 127 |
| 2021 Dezembro | 37 | 52 | 89 |
| 2021 Novembro | 34 | 60 | 94 |
| 2021 Outubro | 50 | 81 | 131 |
| 2021 Setembro | 39 | 48 | 87 |
| 2021 Agosto | 49 | 59 | 108 |
| 2021 Julho | 41 | 44 | 85 |
| 2021 Junho | 36 | 61 | 97 |
| 2021 Maio | 50 | 70 | 120 |
| 2021 Abril | 124 | 226 | 350 |
| 2021 Março | 126 | 79 | 205 |
| 2021 Fevereiro | 28 | 22 | 50 |
| 2021 Janeiro | 39 | 20 | 59 |
| 2020 Dezembro | 18 | 24 | 42 |
| 2020 Novembro | 31 | 21 | 52 |
| 2020 Outubro | 10 | 13 | 23 |
| 2020 Setembro | 10 | 11 | 21 |
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