Treatment of Graves’ ophthalmopathy | Medicina Clínica (English Edition)

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B: la misma paciente de la figura A tras el tratamiento con selenio. Obsérvese la mejoría del edema de partes blandas y la normalización de la retracción del párpado superior derecho. C: Paciente con orbitopatía tiroidea moderada-grave activa con exoftalmos y retracción del párpado superior bilateral, e inflamación orbitaria con hiperemia y edema palpebral y conjuntival. D: el mismo paciente de la figura C 6 meses tras el tratamiento con bolos de glucocorticoides. Se ha inactivado la enfermedad con desaparición de los signos inflamatorios y mejoría parcial de la gravedad (fotografías reproducidas con consentimiento de los pacientes)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Andrés González-García, Marco Sales-Sanz" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Andrés" "apellidos" => "González-García" ] 1 => array:2 [ "nombre" => "Marco" "apellidos" => "Sales-Sanz" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020621000176" "doi" => "10.1016/j.medcle.2020.07.021" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621000176?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320306485?idApp=UINPBA00004N" "url" => "/00257753/0000015600000004/v1_202102130626/S0025775320306485/v1_202102130626/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020621000164" "issn" => "23870206" "doi" => "10.1016/j.medcle.2020.04.029" "estado" => "S300" "fechaPublicacion" => "2021-02-26" "aid" => "5201" "copyright" => "Elsevier España, S.L.U." 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"documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2021;156:177-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial article" "titulo" => "Who should be vaccinated against COVID-19 first?" 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Servicio de Oftalmología, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento de la oftalmopatía de Graves" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1351 "Ancho" => 900 "Tamanyo" => 166962 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Patient with thyroid eye disease in active phase (A). Note chemosis and orbital oedema. There is exophthalmos and strabismus. B: In the inactive phase after treatment with glucocorticoid boluses and tocilizumab. The disease is inactive, but fibrosis sequelae persist. C: After rehabilitative surgery with orbital decompression, strabismus surgery and eyelid retraction surgery. It largely succeeds in restoring the patient's pre-disease normal appearance (photographs shown with the consent of the patient)." ] ] ] "textoCompleto" => "IntroductionGraves' ophthalmopathy (GO) or thyroid eye disease is an immune-mediated disease with involvement of the extraocular muscles, orbital fat and connective tissue.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> It is generally considered to be the main extra-thyroid manifestation of Graves' disease and is clinically relevant in one out of every 20 patients with hyperthyroidism.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> However, almost half of patients with Graves' disease will have clinical characteristics suggestive of GO, so it is essential to distinguish early between moderate and severe forms, mainly those that can lead to corneal ulceration or compression of the optic nerve, and as ultimately loss of vision.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> On the other hand, although less common, ocular inflammation may appear in euthyroid individuals or in hypothyroidism in the context of Hashimoto's thyroiditis.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Although some speculate that there is a genetic basis for the development of GO,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> this has not yet been clearly established in the various studies carried out.GO is usually a single, self-limiting episode that can be divided into 2 phases, depending on the inflammatory activity of the disease. The active, inflammatory phase, depending on the degree of involvement, usually responds to an immunosuppressive anti-inflammatory treatment. During the inactive phase, or sequelae phase, patients can experience aesthetic and functional abnormalities derived from the effects of GO, such as exophthalmos or diplopia. In these cases, immunosuppressive treatment is not recommended due to its limited effectiveness. On the other hand, there are functional or aesthetic sequelae which can be resolved or improved with rehabilitative surgery.In general, mild forms can go unnoticed, and with time even resolve without sequelae (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). However, in most cases, these patients may present cosmetic issues that compromise their quality of life.<a class="elsevierStyleCrossRef" href="#bib0030">6</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>In moderate-severe forms, it is essential to establish an early immunosuppressive treatment that limits the progression of the inflammatory disease. Control of thyroid disease can help to improve orbital involvement,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> although the course is usually independent in most cases.The main clinical manifestations initially consist of a change in appearance, mainly due to upper eyelid retraction and eyelid oedema. In more severe cases there is chemosis, blurred vision and a sensation of pressure or even pain in the retro-ocular area. Subsequently, they usually develop exophthalmos, fatigue and discomfort when reading, as well as pain with eye movements and diplopia. If the condition is severe, there may be a decrease in visual acuity, a reduction in the visual field or a Marcus Gunn pupil, findings that indicate a probable involvement of the optic nerve<a class="elsevierStyleCrossRefs" href="#bib0015">3,8</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Non-pharmacological measures. Favourable and prognostic factorsThe main modifiable environmental factor that produces a worse prognosis in patients with GO is smoking.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> The intensity of the ocular involvement is closely related to the level of smoking and its persistence. Smoking cessation is especially important in these patients. The effectiveness of medical advice to quit smoking in patients with GO resulted in smoking cessation in 42% of the patients in our setting, and the consumption of cigarettes decreased in another 30%.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>As already mentioned, thyroid hormone control is an important factor for the good progression of GO. In addition, euthyroidism favours a good postoperative progression after rehabilitative surgery in the non-active phase of GO.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Among the treatments available for Graves' disease, it has been observed that antithyroid drugs and complete removal of the thyroid gland do not modify the course of the eye disease<a class="elsevierStyleCrossRef" href="#bib0060">12</a>; a different situation occurs with radioactive iodine treatment, where a clear relationship with worsening GO is reported.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> This association has been so strong and widely described,<a class="elsevierStyleCrossRef" href="#bib0070">14</a> that it is recommended that patients at high risk of developing or initiating GO (smokers, hyperthyroidism with poor control, remarkably high thyroid-stimulating hormone [TSH] antibodies) receive prophylaxis with oral glucocorticoids (GC) at medium doses (0.2 mg/kg) for 6 weeks.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> However, it has been observed that total thyroid ablation, compared with a partial thyroidectomy, significantly and promptly improves the activity of GO, both in mild and moderate-severe cases. However, there is insufficient evidence to offer this treatment systematically to patients with Graves' disease.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Drug therapy<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> describes the main characteristics and treatment recommendations for GO. Each of the treatments used to control inflammation are detailed below.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>GlucocorticoidsThey are the mainstay of anti-inflammatory treatment in GO. Regarding the route of administration, the oral and parenteral options have been evaluated, with the latter being in the form of a mega-dose, which has been shown to be more effective than chronic oral therapy,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> with fewer adverse reactions.<a class="elsevierStyleCrossRefs" href="#bib0085">17–19</a>The overall response of the main studies with intravenous GC pulses is around 70–80% of responding patients.<a class="elsevierStyleCrossRefs" href="#bib0085">17,19,20</a> Various intravenous GC dose regimens have been used, with variable cumulative doses between 4.5 g and 12 g, and occasionally with associated oral GC during infusions or after treatment completion, although its use is generally discouraged. Increased treatment doses have been shown to be more effective in terms of outcomes, resulting in increased adverse reactions.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> According to the recommendations of the European Group on Graves Orbitopathy (EUGOGO), and based on our experience, the Kahaly et al. regimen<a class="elsevierStyleCrossRef" href="#bib0085">17</a> seems to be the most effective in terms of achieving clinical improvement with fewer adverse reactions (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D). This regimen consists of the administration of a 500 mg methylprednisolone bolus once a week for 6 weeks, then lower the dose to 250 mg once a week for another 6 weeks. The total dose would be 4.5 g, so it would be very difficult to reach hepatotoxic doses. This fatal adverse reaction was observed using doses greater than 8 g,<a class="elsevierStyleCrossRef" href="#bib0105">21</a> and in some rare case of coexistence with autoimmune hepatitis, in which a rebound phenomenon occurred after GC treatment discontinuation.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> In this sense, it is particularly important to warn about polypharmacy with other hepatotoxic drugs (non-steroidal anti-inflammatory drugs, statins, etc.), as well as antithyroid drugs that, in many cases, are administered together.In addition to the regimen recommended by EUGOGO there is another alternative regimen consisting of 3 pulses of 1 g of methylprednisolone monthly for 6 months with an efficacy similar to the standard regimen, with no major side reactions.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> In cases of optic neuropathy in the active phase, the use of 1 g during 3 consecutive days is recommended; and if they respond, repeat the regimen a week later.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>The administration of GC locally through peribulbar injections has been shown to reduce the inflammatory signs of moderate GO, with reductions in diplopia and muscle size.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> However, there are studies that suggest little efficacy in the use of periocular injections.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>RadiotherapyLocal radiotherapy is considered as salvage therapy, which can be useful in association with GC. The most common dose is usually 2000 rads (20 Gy) in the retro-orbital area, administered in 10 sessions of 200 rads (2 Gy) over 2 weeks. A meta-analysis demonstrated its usefulness to improve symptoms such as diplopia and inflammatory involvement of the GO.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> However, there are studies that doubt its usefulness.<a class="elsevierStyleCrossRefs" href="#bib0135">27,28</a> Post-radiotherapy worsening has been described, which would be controlled with low doses of GC and should not be interpreted as treatment failure. In relation to the radiotherapy technique used, there do not seem to be many differences between volumetric modulated therapy versus intensity-modulated radiation therapy, although the latter seems to provide greater safety.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> In routine clinical practice, the role of radiotherapy would be relegated to those patients with a lack of adequate response to corticosteroid therapy, where this treatment associated with GC at lower doses (half the dose of the Kahaly et al. regimen) could help to control symptoms. Although it is generally safe and well tolerated, there is a risk of causing retinopathy, especially in diabetic patients.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>MycophenolateMycophenolate in its sodium or mofetil formulation has been used extensively in various systemic autoimmune diseases,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> despite the fact that it is only indicated to prevent rejection in solid organ transplantation. Its ease of dosage (oral), together with its safety and good tolerance, facilitate adherence to treatment. Regarding GO treatment, it has been used either exclusively<a class="elsevierStyleCrossRef" href="#bib0160">32</a> or in combination with GC.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> In this last scenario, the moderate-to-severe Graves' orbitopathy study demonstrated that the use of mycophenolate sodium at doses of 360 mg every 12 h, together with intravenous GC, obtained higher response rates at the end of the follow-up with a very adequate adverse reaction profile. However, relapse rates were similar in the 2 groups, so its role as a second-line drug is unclear, and further studies may need to be conducted to establish its definitive role. Regarding monotherapy with mycophenolate, a situation which may arise in those patients with GC intolerance, we only have one study carried out in China, where the outcomes were better compared to GC treatment.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> However, the study's methodology has been criticized for not performing adequate blinding. In addition, cases of optic neuropathy were detected in patients who had received mycophenolate, which again requires further studies to reveal its true effectiveness.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>RituximabIt is a monoclonal antibody that blocks CD20, which is expressed in the B lymphocyte. Its fundamental use comes from experience in the haematology-oncology field, where it revolutionized the treatment approach of many lymphoproliferative disorders, as well as in the field of systemic autoimmune diseases. Regarding GO, it was speculated that its usefulness could be important, given that it is a disease mediated by antibodies against the TSH receptor. However, it was observed that, with B cell depletion treatment, the levels of antibodies are not modified, which suggests that the mode of action in this disease should involve T cell activity modulation.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> It was the first biological treatment used in GO, after several case series, which suggested an improved clinical activity score. Two clinical trials were conducted, the results of which were contradictory. In one of them, no differences were found in the clinical activity of the disease between treatment with rituximab (total dose of 2 g) and placebo.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> In contrast, Salvi et al. showed that rituximab (at doses of 0.5 g and 2 g) had improved disease activity and led to greater inactivation of GO compared to high doses of intravenous GC (7.5 g).<a class="elsevierStyleCrossRef" href="#bib0185">37</a> There has been much speculation about the reason for these 2 conflicting results. In a post hoc analysis using the EUGOGO criteria, the authors of both trials propose that the results were not significantly different. They also attribute the different results to differences in the sample, with younger patients, with a shorter duration of the disease, with lower levels of anti-TSH receptor antibodies in the European trial, as well as differences in smoking habits.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> It is important to highlight that cases of dysthyroid optic neuropathy were observed in one of the studies, and that one of them was related to the release of cytokines, a condition which improved with the steroid treatment. It seems that this treatment can work in those patients with active GO and if the course of the disease is short.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Currently the EUGOGO guidelines recommend rituximab in patients refractory to steroid treatment.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>TocilizumabTocilizumab is a monoclonal antibody that blocks the interleukin 6 (IL-6) receptor and is used as a biologic drug in the treatment of autoinflammatory diseases and systemic autoimmune diseases, such as rheumatoid arthritis and giant cell arteritis.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> IL-6 is a ubiquitous protein in the body and highly involved in the control of the inflammatory response. In GO, it has a relevant role as an inducer of local inflammation in relation to the increase in the expression of the thyrotropin receptor in the orbital connective tissue.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> After the favourable reaction and clinical progression of cases with active GO that responded to treatment with tocilizumab, a randomized double-blind clinical trial with placebo was conducted in our country that demonstrated the improvement in activity in patients with GC-refractory GO<a class="elsevierStyleCrossRef" href="#bib0205">41</a>. However, no significant difference was found in exophthalmos reduction at week 40 compared to placebo. The trial used doses of 8 mg/kg, monthly, in intravenous formulation for 4 months. There are, however, other studies where subcutaneous parenteral administration at doses of 162 mg for a total of 4 doses, which can be given weekly (if weight > 100 kg) or every 15 days (weight < 100 kg), has demonstrated safety and efficacy in GO inflammation control.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>TeprotumumabIt is a humanized monoclonal antibody against the G1 immunoglobulin subclass. It acts by binding to the insulin growth factor 1 (IGF1R) receptor, acting as a powerful inhibitor of the activation of IGF1R signalling, which is over-expressed in orbital fibroblasts and which plays a particularly important role in GO inflammation.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3,43,44</a> There are 2 clinical trials of teprotumumab for GO with very positive results compared to placebo,<a class="elsevierStyleCrossRefs" href="#bib0225">45,46</a> which has prompted its approval by the Food and Drug Administration for the treatment of GO.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> In the former, up to 69% of patients in the drug group showed significant improvements in the clinical activity score. Regarding safety, the patients developed infectious and gastrointestinal events, and there was one case of immune-mediated encephalopathy.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> The second pivotal study was carried out in patients with recently diagnosed GO (up to 9 months of previous symptoms) and with data of moderate activity, without prior treatment with GC. Those who received teprotumumab had a response rate of 83% compared to 10% in the placebo group, and practically all the secondary endpoints (diplopia, proptosis, quality of life) showed a clinically and statistically significant improvement.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>Treatment consists of administering a first infusion of 10 mg/kg followed by 7 infusions of 20 mg/kg every 3 weeks.Cyclosporine/mTOR inhibitorsThe use of cyclosporine in GO began as a result of its inhibitory action on the T lymphocyte, as it decreased the levels of IL-2. Its use is based on former research when biological therapy did not exist. However, there is evidence that shows that the combination of cyclosporine at doses of 5–7.5 mg/kg with GC versus cyclosporine monotherapy shows superiority in terms of clinical activity.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Treatment with cyclosporine is usually reserved for cases refractory to GC, radiotherapy, or other biological therapy. Its adverse reactions (kidney toxicity, high blood pressure, risk of infections) and the fact that it requires a long-term treatment greatly limit its use.Other treatments for Graves' ophthalmopathyGiven their potential immunosuppressive effect, treatments such as methotrexate, azathioprine, and intravenous immunoglobulins have been used with little clinical impact, or with anecdotal benefit.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> Methotrexate has been analysed in retrospective studies in combination with GC with the intention of taking advantage of its GC-sparing effect.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> However, its potential effect in patients without steroid treatment is unknown. Intravenous immunoglobulins can be used in refractory situations, when potent immunosuppressive treatments have been used and further immunosuppression is not desired, since they have been shown to be effective in a similar way to GC.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Its cost and the need to maintain therapy for several months makes it necessary to limit this treatment to exceptional situations. As in biological therapy with rituximab and teprotumumab, anti-tumour necrosis factor treatments have previously been used 〈 (adalimumab, etanercept and infliximab) in isolated cases with not very robust results.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Role of surgery in Graves' ophthalmopathySurgery in GO is indicated in the acute phase to treat compressive optic neuropathy that does not respond to GC or corneal exposure refractory to conservative measures, and in the inactive phase to treat any sequelae that produces an alteration in the quality of life and a candidate for surgical improvement. Surgery in the inactive phase in cases of eyelid retraction or exophthalmos should not be considered cosmetic but rehabilitative surgery, since patients do not try to gain beauty, but to have their eyes as similar as possible to what they were before the disease.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> Surgery in GO has been shown to greatly improve the quality of life of patients.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>Rehabilitative surgery consists of one or more of the following procedures: orbital decompression to correct the exophthalmos, surgery of the extraocular muscles to correct strabismus, and upper eyelid levator muscle or Müller's muscle weakening surgery to correct eyelid retraction. Eyelid surgery may also require performing posterior lamina grafts to treat lower eyelid retraction, or lipectomies to correct excess orbital fat and retro-orbicularis oculi fat (ROOF) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Since the first description of the use of orbital decompression in GO, multiple variants of the technique have been described. Very few of these articles have sufficient scientific rigor to represent high-level clinical evidence, so literature reviews can only summarize the techniques described, and provide general concepts of efficacy and complications. In general, orbital decompression has good results in correcting the exophthalmos, with a tolerable complication profile.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>With regard to strabismus surgery, achieving a field of single binocular vision in the primary position and infraversion with a single surgical intervention is recommended. As it is a restrictive strabismus, it is recommended to perform weakening procedures, mainly retro-insertions. There are different nomograms and techniques to estimate which is the optimal weakening procedure, but none has shown clear superiority over the others.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>For the correction of eyelid retraction, as it happens with the other rehabilitative surgeries for GO, there is no single common technique for all cases. There are multiple techniques that act on Müller's muscle and/or the levator muscle of the upper eyelid.<a class="elsevierStyleCrossRefs" href="#bib0120">24,54</a>ConclusionsGO is an autoimmune inflammatory disease that usually occurs in a single self-limiting exacerbation lasting a couple of years.The active phase is treated medically, and the drugs used depend on the severity of the disease. Mild cases are treated with selenium and general measures. Moderate-severe cases are treated first-line with intravenous GC. In cases of resistance or recurrence, the most widely used second-line treatments are radiotherapy and biological drugs such as teprotumumab, tocilizumab or rituximab. In vision-threatening cases, GC treatment must be administered at high doses, and salvage surgical orbital decompression is often required. Smoking cessation is especially important to control disease activity.The sequelae of GO in the inactive phase can be treated with surgery, significantly improving the quality of life of patients. Immunosuppressive treatment is not recommended in this phase.Conflict of interestsThe authors declare that they have no conflict of interest regarding the publication of this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1466985" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1336334" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1466986" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1336335" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Non-pharmacological measures. Favourable and prognostic factors" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Drug therapy" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Glucocorticoids" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Radiotherapy" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Mycophenolate" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Rituximab" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Tocilizumab" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Teprotumumab" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Cyclosporine/mTOR inhibitors" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Other treatments for Graves' ophthalmopathy" ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Role of surgery in Graves' ophthalmopathy" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-05-24" "fechaAceptado" => "2020-07-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1336334" "palabras" => array:7 [ 0 => "Graves-Basedow disease" 1 => "Graves' ophthalmopathy" 2 => "Orbitopathy" 3 => "Glucocorticoids" 4 => "Teprotumumab" 5 => "Rituximab" 6 => "Tocilizumab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1336335" "palabras" => array:7 [ 0 => "Enfermedad de Graves-Basedow" 1 => "Inflamación orbitaria" 2 => "Orbitopatía" 3 => "Glucocorticoides" 4 => "Teprotumumab" 5 => "Rituximab" 6 => "Tocilizumab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Graves' ophthalmopathy is an inflammatory disease with primary involvement of the extraocular muscles and the orbit. It encompasses the most common extra-thyroid manifestation in patients with Graves-Basedow disease. The underlying cause is molecular mimicry with the TSH receptor in ocular fibroblasts, leading to an immuno-mediated pathogenesis. Glucocorticoids at high doses are the cornerstone in moderate-severe cases. However, some patients are corticorresistant or intolerant. In recent years, therapeutic novelties have been described in terms of the dosage of the immunosuppressive treatments used, as well as the emergence of biological therapy in this field. The objective of this review is to update the treatment of Graves’ ophthalmopathy, as well as to present alternative options in patients resistant or intolerant to glucocorticoids." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La oftalmopatía de Graves constituye una enfermedad inflamatoria con afectación fundamental de los músculos extraoculares y de la órbita, y representa la principal manifestación extratiroidea en los pacientes con enfermedad de Graves-Basedow. La etiopatogenia subyacente es inmunomediada mediante un mimetismo molecular con el receptor de la TSH en los fibroblastos oculares. El principal tratamiento en los casos moderados-graves se basa en la inmunosupresión sistémica, y son de elección los glucocorticoides a dosis altas. Sin embargo, algunos pacientes presentan intolerancia al tratamiento o mala respuesta a los glucocorticoides. En los últimos años se han descrito novedades terapéuticas en cuanto a la posología de los tratamientos inmunosupresores empleados, así como la irrupción de la terapia biológica en este campo. El objetivo de esta revisión es actualizar el tratamiento de la oftalmopatía inflamatoria, así como presentar opciones terapéuticas alternativas en aquellos casos corticoresistentes o con intolerancia a glucocorticoides." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: González-García A, Sales-Sanz M. Tratamiento de la oftalmopatía de Graves. Med Clin (Barc). 2021;156:180–186." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 679 "Ancho" => 1250 "Tamanyo" => 130728 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "A: Patient with mild active thyroid eye disease, with slight right exophthalmos, retraction of the upper right eyelid and minimal bilateral soft tissue oedema. B: the same patient in figure A after treatment with selenium. Note the improvement in soft tissue oedema and the return to normality of the right upper eyelid retraction. C: Patient with active moderate-severe thyroid eye disease with exophthalmos and bilateral upper eyelid retraction, and orbital inflammation with hyperaemia and eyelid and conjunctival oedema. D: the same patient in figure C 6 months after glucocorticoid bolus treatment. The disease has been inactivated with disappearance of inflammatory signs and partial improvement in severity (photographs shown with the consent of the patients)." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1351 "Ancho" => 900 "Tamanyo" => 166962 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Patient with thyroid eye disease in active phase (A). Note chemosis and orbital oedema. There is exophthalmos and strabismus. B: In the inactive phase after treatment with glucocorticoid boluses and tocilizumab. The disease is inactive, but fibrosis sequelae persist. C: After rehabilitative surgery with orbital decompression, strabismus surgery and eyelid retraction surgery. It largely succeeds in restoring the patient's pre-disease normal appearance (photographs shown with the consent of the patient)." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "DON: Dysthyroid Optic Neuropathy." "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">Forms \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">Characteristics and recommendations \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">Mild \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">Those that do not alter quality of life sufficiently to justify treatment with systemic glucocorticoidsEyelid retraction under 2 mmMild soft tissue involvementExophthalmos under 3 mmMinimal corneal involvement that responds to lubricantsA mild transient diplopiaFavourable progression with watchful waitingLocal measures with topical lubricants/ocular occlusion during night restSelenium (100 mg every 12 h for 6 months) \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">Moderate-severe \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">These forms are those that do not exhibit any signs of risk to vision and that the quality of life is affected to the point of requiring immunosuppressive therapy to control the inflammatory processGlucocorticoid pulses (Kahaly's regimen)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">Severe \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">DON. Optic nerve involvementDecreased visual acuityMarcus Gunn pupilColour vision deficiencyPapilledemaVisual field defectsApical crowding on the radiographic imageMethylprednisolone pulses 500−1,000 mg daily for 3 days followed by decompressive surgery \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2524042.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Kahaly's regimen: 500 mg of intravenous methylprednisolone weekly for 6 weeks, and subsequently 250 mg of intravenous methylprednisolone weekly for an additional 6 weeks." ] ] ] "descripcion" => array:1 [ "en" => "Classification and treatment recommendations in Graves' ophthalmopathy." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "HbA1c: glycated haemoglobin; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; iv: intravenous; sc: subcutaneous; HBV: hepatitis B virus; HCV: hepatitis C virus." "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">Treatment \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">Pre-screening \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">Dose \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">Monitoring \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">Glucocorticoids \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">HbA1c, Glucose, liver profileHBV, HCV serologiesScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \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">500 mg iv (first 6 weeks)250 mg iv (next 6 weeks) \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">Liver profile at 1−2 months and after the end of treatment \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">Mycophenolate \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">Complete blood count, liver profileHBV, HCV serologiesScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \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">360 mg every 12 h<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a> orally OR 1 g every 12 hours<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a> orally 24 weeks \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">Complete blood count and liver profile every 6−8 weeks \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">Rituximab \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">HBV, HCV serologiesIgG, IgA, IgM immunoglobulinsScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 doses of 1 g spread over 14 days \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">Complete blood count (per month)IgG, IgA, IgM immunoglobulins \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">Tocilizumab \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">Liver profileComplete blood countHBV, HCV serologiesScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \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">8 mg/kg monthly (4 months<a class="elsevierStyleCrossRef" href="#tblfn0025">d</a>) iv or 162 mg weekly/biweekly sc \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">Lipoprotein electrophoresisLiver profileComplete blood count \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">Teprotumumab \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">HbA1c, blood glucoseKidney function, liver profileComplete blood countHBV, HCV serologies \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">Every 3 weeks20 mg/kg first dose iv. Subsequently 10 mg/kg iv up to a total of 8 \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">GlucoseLiver profile, blood count \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2524043.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "It is recommended to perform a chest X-ray, tuberculin or quantiferon test, to rule out tuberculosis disease. In case of positive Mantoux test or IGRA with no evidence of disease, perform chemoprophylaxis." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "Mycophenolate sodium." ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "Mycophenolate mofetil." ] 3 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "d" "nota" => "If there is a good response, but persistence of inflammation, an extension of the treatment time might be considered." ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for monitoring drugs used in Graves' ophthalmopathy." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:54 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Understanding the immunology of Graves’ ophthalmopathy. Is it an autoimmune disease?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.S. Bahn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0889-8529(05)70132-8" "Revista" => array:6 [ "tituloSerie" => "Endocrinol Metab Clin North Am" "fecha" => "2000" "volumen" => "29" "paginaInicial" => "287" "paginaFinal" => "296" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10874530" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "W.M. Wiersinga" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(16)30046-8" "Revista" => array:6 [ "tituloSerie" => "Lancet Diabetes Endocrinol" "fecha" => "2017" "volumen" => "5" "paginaInicial" => "134" "paginaFinal" => "142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27346786" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.S. Bahn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra0905750" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2010" "volumen" => "362" "paginaInicial" => "726" "paginaFinal" => "738" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20181974" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.H. Khoo" 1 => "P.H. Eng" 2 => "S.C. Ho" 3 => "E.S. Tai" 4 => "N.G. Morgenthaler" 5 => "L.L. Seah" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/thy.2000.10.1093" "Revista" => array:6 [ "tituloSerie" => "Thyroid" "fecha" => "2000" "volumen" => "10" "paginaInicial" => "1093" "paginaFinal" => "1100" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11201855" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic factors in Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Frecker" 1 => "V. Stenszky" 2 => "C. Balazs" 3 => "L. Kozma" 4 => "E. Kraszits" 5 => "N.R. Farid" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "1986" "volumen" => "25" "paginaInicial" => "479" "paginaFinal" => "485" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quality of life in Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "W.M. Wiersinga" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Best Pract Res Clin Endocrinol Metab" "fecha" => "2012" "volumen" => "26" "paginaInicial" => "359" "paginaFinal" => "370" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of abnormal thyroid function on the severity of Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.F. Prummel" 1 => "W.M. Wiersinga" 2 => "M.P. Mourits" 3 => "L. Koornneef" 4 => "A. Berghout" 5 => "R. van der Gaag" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1990" "volumen" => "150" "paginaInicial" => "1098" "paginaFinal" => "1101" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1691908" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G.B. Bartley" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Trans Am Ophthalmol Soc" "fecha" => "1994" "volumen" => "92" "paginaInicial" => "477" "paginaFinal" => "588" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7886878" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smoking and thyroid disorders–a meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. Vestergaard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/eje.0.1460153" "Revista" => array:6 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "2002" "volumen" => "146" "paginaInicial" => "153" "paginaFinal" => "161" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11834423" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effectiveness of oral counselling for smoke cessation in Graves orbitopathy patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P. de-Arriba-Palomero" 1 => "M. Sales-Sanz" 2 => "E. Fuentemilla" 3 => "H.R. Won-Kim" 4 => "F. de-Arriba-Palomero" 5 => "F.J. Muñoz-Negrete" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.oftal.2019.03.008" "Revista" => array:6 [ "tituloSerie" => "Arch Soc Esp Oftalmol" "fecha" => "2019" "volumen" => "94" "paginaInicial" => "323" "paginaFinal" => "330" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31036428" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medical Treatment of Graves’ Orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Salvi" 1 => "I. Campi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0035-1554721" "Revista" => array:6 [ "tituloSerie" => "Horm Metab Res" "fecha" => "2015" "volumen" => "47" "paginaInicial" => "779" "paginaFinal" => "788" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26361263" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The course of Graves’ ophthalmopathy is not influenced by near total thyroidectomy: a case-control study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Marcocci" 1 => "G. Bruno-Bossio" 2 => "L. Manetti" 3 => "M.L. Tanda" 4 => "P. Miccoli" 5 => "P. Iacconi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "1999" "volumen" => "51" "paginaInicial" => "503" "paginaFinal" => "508" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.H. Acharya" 1 => "A. Avenell" 2 => "S. Philip" 3 => "J. Burr" 4 => "J.S. Bevan" 5 => "P. Abraham" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "2008" "volumen" => "69" "paginaInicial" => "943" "paginaFinal" => "950" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Occurrence of ophthalmopathy after treatment for Graves’ hyperthyroidism. The Thyroid Study Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Tallstedt" 1 => "G. Lundell" 2 => "O. Torring" 3 => "G. Wallin" 4 => "J.G. Ljunggren" 5 => "H. Blomgren" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199206253262603" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1992" "volumen" => "326" "paginaInicial" => "1733" "paginaFinal" => "1738" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1489388" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent graves’ orbitopathy: a retrospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Lai" 1 => "L. Sassi" 2 => "E. Compri" 3 => "F. Marino" 4 => "P. Sivelli" 5 => "E. Piantanida" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2009-2130" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2010" "volumen" => "95" "paginaInicial" => "1333" "paginaFinal" => "1337" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20061414" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relation between therapy options for Graves’ disease and the course of Graves’ ophthalmopathy: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H.X. Li" 1 => "N. Xiang" 2 => "W.K. Hu" 3 => "X.L. Jiao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40618-016-0484-y" "Revista" => array:6 [ "tituloSerie" => "J Endocrinol Invest" "fecha" => "2016" "volumen" => "39" "paginaInicial" => "1225" "paginaFinal" => "1233" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27220843" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G.J. Kahaly" 1 => "S. Pitz" 2 => "G. Hommel" 3 => "M. Dittmar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2005-0148" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2005" "volumen" => "90" "paginaInicial" => "5234" "paginaFinal" => "5240" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15998777" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High-dose intravenous corticosteroid therapy for Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P.E. Macchia" 1 => "M. Bagattini" 2 => "G. Lupoli" 3 => "M. Vitale" 4 => "G. Vitale" 5 => "G. Fenzi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/BF03343835" "Revista" => array:6 [ "tituloSerie" => "J Endocrinol Invest" "fecha" => "2001" "volumen" => "24" "paginaInicial" => "152" "paginaFinal" => "158" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11314743" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment modalities for Graves’ ophthalmopathy: systematic review and metaanalysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. Stiebel-Kalish" 1 => "E. Robenshtok" 2 => "M. Hasanreisoglu" 3 => "D. Ezrachi" 4 => "I. Shimon" 5 => "L. Leibovici" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2009-0376" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2009" "volumen" => "94" "paginaInicial" => "2708" "paginaFinal" => "2716" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19491222" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves’ orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Bartalena" 1 => "G.E. Krassas" 2 => "W. Wiersinga" 3 => "C. Marcocci" 4 => "M. Salvi" 5 => "C. Daumerie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2012-2389" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2012" "volumen" => "97" "paginaInicial" => "4454" "paginaFinal" => "4463" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23038682" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute liver damage following intravenous glucocorticoid treatment for Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Moleti" 1 => "G. Giuffrida" 2 => "G. Sturniolo" 3 => "G. Squadrito" 4 => "A. Campennì" 5 => "S. Morelli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12020-016-0928-3" "Revista" => array:6 [ "tituloSerie" => "Endocrine" "fecha" => "2016" "volumen" => "54" "paginaInicial" => "259" "paginaFinal" => "268" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27003434" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Marino" 1 => "E. Morabito" 2 => "M.R. Brunetto" 3 => "L. Bartalena" 4 => "A. Pinchera" 5 => "C. Marocci" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/105072504774193276" "Revista" => array:6 [ "tituloSerie" => "Thyroid" "fecha" => "2004" "volumen" => "14" "paginaInicial" => "403" "paginaFinal" => "406" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15186621" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of pulsed intravenous methylprednisolone in early active thyroid eye disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.M. Young" 1 => "A.Y.N. Lim" 2 => "S.S. Lang" 3 => "K.O. Lee" 4 => "G. Sundar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/01676830.2018.1553189" "Revista" => array:6 [ "tituloSerie" => "Orbit" "fecha" => "2019" "volumen" => "38" "paginaInicial" => "362" "paginaFinal" => "369" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30540214" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Bartalena" 1 => "L. Baldeschi" 2 => "K. Boboridis" 3 => "A. Eckstein" 4 => "G.J. Kahaly" 5 => "C. Marcocci" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000443828" "Revista" => array:6 [ "tituloSerie" => "Eur Thyroid J" "fecha" => "2016" "volumen" => "5" "paginaInicial" => "9" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27099835" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Repeated peribulbar injections of triamcinolone acetonide: a successful and safe treatment for moderate to severe Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Bordaberry" 1 => "D.L. Marques" 2 => "J.C. Pereira-Lima" 3 => "I.M. Marcon" 4 => "H. Schmid" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1755-3768.2008.01171.x" "Revista" => array:6 [ "tituloSerie" => "Acta Ophthalmol" "fecha" => "2009" "volumen" => "87" "paginaInicial" => "58" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18937809" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Orbital steroid injections" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.A. Goldberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bjo.2004.051755" "Revista" => array:6 [ "tituloSerie" => "Br J Ophthalmol" "fecha" => "2004" "volumen" => "88" "paginaInicial" => "1359" "paginaFinal" => "1360" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15489472" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Radiotherapy for Graves’ orbitopathy: randomised placebo-controlled study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.P. Mourits" 1 => "M.L. van Kempen-Harteveld" 2 => "M.B. Garcia" 3 => "H.P. Koppeschaar" 4 => "L. Tick" 5 => "C.B. Terwee" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "2000" "volumen" => "355" "paginaInicial" => "1505" "paginaFinal" => "1509" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.A. Gorman" 1 => "J.A. Garrity" 2 => "V. Fatourechi" 3 => "R.S. Bahn" 4 => "I.A. Petersen" 5 => "S.L. Stafford" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Ophthalmology" "fecha" => "2001" "volumen" => "108" "paginaInicial" => "1523" "paginaFinal" => "1534" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of IMRT and VMAT radiotherapy planning for Graves’ ophthalmopathy based on dosimetric parameters analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.C. Wang" 1 => "J. Wu" 2 => "X.Q. Xie" 3 => "X.L. Liu" 4 => "Y. Luo" 5 => "F. Wang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.26355/eurrev_202004_20856" "Revista" => array:6 [ "tituloSerie" => "Eur Rev Med Pharmacol Sci" "fecha" => "2020" "volumen" => "24" "paginaInicial" => "3898" "paginaFinal" => "3906" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32329865" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term safety of orbital radiotherapy for Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Marcocci" 1 => "L. Bartalena" 2 => "R. Rocchi" 3 => "M. Marinò" 4 => "F. Menconi" 5 => "E. Morabito" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2003-030260" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2003" "volumen" => "88" "paginaInicial" => "3561" "paginaFinal" => "3566" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12915636" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.C.A. Broen" 1 => "J.M. van Laar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41584-020-0374-8" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Rheumatol" "fecha" => "2020" "volumen" => "16" "paginaInicial" => "167" "paginaFinal" => "178" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32055040" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X. Ye" 1 => "X. Bo" 2 => "X. Hu" 3 => "H. Cui" 4 => "B. Lu" 5 => "J. Shao" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "2017" "volumen" => "86" "paginaInicial" => "247" "paginaFinal" => "255" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.J. Kahaly" 1 => "M. Riedl" 2 => "J. Konig" 3 => "S. Pitz" 4 => "K. Ponto" 5 => "T. Diana" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(18)30020-2" "Revista" => array:6 [ "tituloSerie" => "Lancet Diabetes Endocrinol" "fecha" => "2018" "volumen" => "6" "paginaInicial" => "287" "paginaFinal" => "298" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29396246" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prospective, systematically recorded mycophenolate safety data in Graves’ orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Riedl" 1 => "A. Kuhn" 2 => "I. Kramer" 3 => "E. Kolbe" 4 => "G.J. Kahaly" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40618-016-0441-9" "Revista" => array:6 [ "tituloSerie" => "J Endocrinol Invest" "fecha" => "2016" "volumen" => "39" "paginaInicial" => "687" "paginaFinal" => "694" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26886940" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "B cells in Graves’ Orbitopathy: more than just a source of antibodies?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Salvi" 1 => "D. Covelli" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Eye (Lond)" "fecha" => "2019" "volumen" => "33" "paginaInicial" => "230" "paginaFinal" => "234" ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomized controlled trial of rituximab in patients with Graves’ orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.N. Stan" 1 => "J.A. Garrity" 2 => "B.G. Carranza Leon" 3 => "T. Prabin" 4 => "E.A. Bradley" 5 => "R.S. Bahn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2014-2572" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2015" "volumen" => "100" "paginaInicial" => "432" "paginaFinal" => "441" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25343233" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Salvi" 1 => "G. Vannucchi" 2 => "N. Curro" 3 => "I. Campi" 4 => "D. Covelli" 5 => "D. Dazzi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2014-3014" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2015" "volumen" => "100" "paginaInicial" => "422" "paginaFinal" => "431" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25494967" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves’ orbitopathy - lessons from randomized control trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.N. Stan" 1 => "M. Salvi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1530/EJE-16-0552" "Revista" => array:6 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "2017" "volumen" => "176" "paginaInicial" => "R101" "paginaFinal" => "R109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27760790" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A review of recent advances using tocilizumab in the treatment of rheumatic diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Rubbert-Roth" 1 => "D.E. Furst" 2 => "J.M. Nebesky" 3 => "A. Jin" 4 => "E. Berber" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatol Ther" "fecha" => "2018" "volumen" => "5" "paginaInicial" => "21" "paginaFinal" => "42" ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.C. Jyonouchi" 1 => "R.W. Valyasevi" 2 => "D.A. Harteneck" 3 => "C.M. Dutton" 4 => "R.S. Bahn" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Thyroid" "fecha" => "2001" "volumen" => "11" "paginaInicial" => "929" "paginaFinal" => "934" ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves Orbitopathy: A randomized clinical trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.V. Perez-Moreiras" 1 => "J.J. Gomez-Reino" 2 => "J.R. Maneiro" 3 => "E. Perez-Pampin" 4 => "A. Romo Lopez" 5 => "F.M. Rodríguez Alvarez" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Ophthalmol" "fecha" => "2018" "volumen" => "195" "paginaInicial" => "181" "paginaFinal" => "190" ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Subcutaneous Tocilizumab for Thyroid Eye Disease: Simplified Dosing and Delivery" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "T. Copperman" 1 => "O.O. Idowu" 2 => "R.C. Kersten" 3 => "M.R. Vagefi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Ophthalmic Plast Reconstr Surg" "fecha" => "2019" "volumen" => "35" "paginaInicial" => "e64" "paginaFinal" => "e66" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New insights into the pathogenesis and nonsurgical management of Graves orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.N. Taylor" 1 => "L. Zhang" 2 => "R.W.J. Lee" 3 => "I. Muller" 4 => "D.G. Ezra" 5 => "C.M. Dayan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41574-019-0305-4" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Endocrinol" "fecha" => "2020" "volumen" => "16" "paginaInicial" => "104" "paginaFinal" => "116" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31889140" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T.J. Smith" 1 => "J. Janssen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Endocr Rev" "fecha" => "2019" "volumen" => "40" "paginaInicial" => "236" "paginaFinal" => "267" ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Teprotumumab for Thyroid-Associated Ophthalmopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.J. Smith" 1 => "G.J. Kahaly" 2 => "D.G. Ezra" 3 => "J.C. Fleming" 4 => "R.A. Dailey" 5 => "R.A. Tang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1614949" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2017" "volumen" => "376" "paginaInicial" => "1748" "paginaFinal" => "1761" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28467880" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Teprotumumab for the Treatment of Active Thyroid Eye Disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.S. Douglas" 1 => "G.J. Kahaly" 2 => "A. Patel" 3 => "S. Sile" 4 => "E.H.Z. Thompson" 5 => "R. Perdok" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1910434" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2020" "volumen" => "382" "paginaInicial" => "341" "paginaFinal" => "352" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31971679" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Teprotumumab: First Approval" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. Markham" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Drugs" "fecha" => "2020" "volumen" => "80" "paginaInicial" => "509" "paginaFinal" => "512" ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ciclosporin and prednisone v. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Kahaly" 1 => "J. Schrezenmeir" 2 => "U. Krause" 3 => "B. Schweikert" 4 => "S. Meuer" 5 => "W. Muller" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2362.1986.tb01016.x" "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Invest" "fecha" => "1986" "volumen" => "16" "paginaInicial" => "415" "paginaFinal" => "422" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3100309" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate as an Adjuvant in Severe Thyroid Eye Disease: Does It Really Work as a Steroid-Sparing Agent?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.L. Yong" 1 => "C.L. Chng" 2 => "N. Ming Sie" 3 => "S. Lang" 4 => "M. Yang" 5 => "A. Looi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/IOP.0000000000001279" "Revista" => array:6 [ "tituloSerie" => "Ophthalmic Plast Reconstr Surg" "fecha" => "2019" "volumen" => "35" "paginaInicial" => "369" "paginaFinal" => "373" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30624412" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current and Emerging Treatment Strategies for Graves’ Orbitopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Genere" 1 => "M.N. Stan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40265-018-1045-9" "Revista" => array:6 [ "tituloSerie" => "Drugs" "fecha" => "2019" "volumen" => "79" "paginaInicial" => "109" "paginaFinal" => "124" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30659423" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of quality of life in patients with Graves ophthalmopathy, before and after orbital decompression" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. Iacobaeus" 1 => "S. Sahlin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/01676830.2016.1176049" "Revista" => array:6 [ "tituloSerie" => "Orbit" "fecha" => "2016" "volumen" => "35" "paginaInicial" => "121" "paginaFinal" => "125" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27159575" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Orbital decompression for thyroid eye disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D.B. 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Review

Treatment of Graves’ ophthalmopathy

Tratamiento de la oftalmopatía de Graves

Andrés González-Garcíaa,

Corresponding author

andres.gonzalez@salud.madrid.org

Corresponding author.

, Marco Sales-Sanzb

a Unidad de Enfermedades Sistémicas Autoinmunes y Minoritarias, Servicio de Medicina Interna, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain

b CSUR de tumores orbitarios y cirugía de descompresión orbitaria en Oftalmopatía Tiroidea. Servicio de Oftalmología, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain

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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">Graves&#39; ophthalmopathy &#40;GO&#41; or thyroid eye disease is an immune-mediated disease with involvement of the extraocular muscles&#44; orbital fat and connective tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It is generally considered to be the main extra-thyroid manifestation of Graves&#39; disease and is clinically relevant in one out of every 20 patients with hyperthyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; almost half of patients with Graves&#39; disease will have clinical characteristics suggestive of GO&#44; so it is essential to distinguish early between moderate and severe forms&#44; mainly those that can lead to corneal ulceration or compression of the optic nerve&#44; and as ultimately loss of vision&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> On the other hand&#44; although less common&#44; ocular inflammation may appear in euthyroid individuals or in hypothyroidism in the context of Hashimoto&#39;s thyroiditis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Although some speculate that there is a genetic basis for the development of GO&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> this has not yet been clearly established in the various studies carried out&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">GO is usually a single&#44; self-limiting episode that can be divided into 2 phases&#44; depending on the inflammatory activity of the disease&#46; The active&#44; inflammatory phase&#44; depending on the degree of involvement&#44; usually responds to an immunosuppressive anti-inflammatory treatment&#46; During the inactive phase&#44; or sequelae phase&#44; patients can experience aesthetic and functional abnormalities derived from the effects of GO&#44; such as exophthalmos or diplopia&#46; In these cases&#44; immunosuppressive treatment is not recommended due to its limited effectiveness&#46; On the other hand&#44; there are functional or aesthetic sequelae which can be resolved or improved with rehabilitative surgery&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In general&#44; mild forms can go unnoticed&#44; and with time even resolve without sequelae &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A and B&#41;&#46; However&#44; in most cases&#44; these patients may present cosmetic issues that compromise their quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">In moderate-severe forms&#44; it is essential to establish an early immunosuppressive treatment that limits the progression of the inflammatory disease&#46; Control of thyroid disease can help to improve orbital involvement&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> although the course is usually independent in most cases&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The main clinical manifestations initially consist of a change in appearance&#44; mainly due to upper eyelid retraction and eyelid oedema&#46; In more severe cases there is chemosis&#44; blurred vision and a sensation of pressure or even pain in the retro-ocular area&#46; Subsequently&#44; they usually develop exophthalmos&#44; fatigue and discomfort when reading&#44; as well as pain with eye movements and diplopia&#46; If the condition is severe&#44; there may be a decrease in visual acuity&#44; a reduction in the visual field or a Marcus Gunn pupil&#44; findings that indicate a probable involvement of the optic nerve<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;8</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Non-pharmacological measures&#46; Favourable and prognostic factors</span><p id="par0030" class="elsevierStylePara elsevierViewall">The main modifiable environmental factor that produces a worse prognosis in patients with GO is smoking&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The intensity of the ocular involvement is closely related to the level of smoking and its persistence&#46; Smoking cessation is especially important in these patients&#46; The effectiveness of medical advice to quit smoking in patients with GO resulted in smoking cessation in 42&#37; of the patients in our setting&#44; and the consumption of cigarettes decreased in another 30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">As already mentioned&#44; thyroid hormone control is an important factor for the good progression of GO&#46; In addition&#44; euthyroidism favours a good postoperative progression after rehabilitative surgery in the non-active phase of GO&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Among the treatments available for Graves&#39; disease&#44; it has been observed that antithyroid drugs and complete removal of the thyroid gland do not modify the course of the eye disease<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#59; a different situation occurs with radioactive iodine treatment&#44; where a clear relationship with worsening GO is reported&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This association has been so strong and widely described&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> that it is recommended that patients at high risk of developing or initiating GO &#40;smokers&#44; hyperthyroidism with poor control&#44; remarkably high thyroid-stimulating hormone &#91;TSH&#93; antibodies&#41; receive prophylaxis with oral glucocorticoids &#40;GC&#41; at medium doses &#40;0&#46;2&#8239;mg&#47;kg&#41; for 6 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> However&#44; it has been observed that total thyroid ablation&#44; compared with a partial thyroidectomy&#44; significantly and promptly improves the activity of GO&#44; both in mild and moderate-severe cases&#46; However&#44; there is insufficient evidence to offer this treatment systematically to patients with Graves&#39; disease&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Drug therapy</span><p id="par0040" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> describes the main characteristics and treatment recommendations for GO&#46; Each of the treatments used to control inflammation are detailed below&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Glucocorticoids</span><p id="par0045" class="elsevierStylePara elsevierViewall">They are the mainstay of anti-inflammatory treatment in GO&#46; Regarding the route of administration&#44; the oral and parenteral options have been evaluated&#44; with the latter being in the form of a mega-dose&#44; which has been shown to be more effective than chronic oral therapy&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> with fewer adverse reactions&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The overall response of the main studies with intravenous GC pulses is around 70&#8211;80&#37; of responding patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;19&#44;20</span></a> Various intravenous GC dose regimens have been used&#44; with variable cumulative doses between 4&#46;5&#8239;g and 12&#8239;g&#44; and occasionally with associated oral GC during infusions or after treatment completion&#44; although its use is generally discouraged&#46; Increased treatment doses have been shown to be more effective in terms of outcomes&#44; resulting in increased adverse reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> According to the recommendations of the <span class="elsevierStyleItalic">European Group on Graves Orbitopathy</span> &#40;EUGOGO&#41;&#44; and based on our experience&#44; the Kahaly et al&#46; regimen<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> seems to be the most effective in terms of achieving clinical improvement with fewer adverse reactions &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C and D&#41;&#46; This regimen consists of the administration of a 500&#8239;mg methylprednisolone <span class="elsevierStyleItalic">bolus</span> once a week for 6 weeks&#44; then lower the dose to 250&#8239;mg once a week for another 6 weeks&#46; The total dose would be 4&#46;5&#8239;g&#44; so it would be very difficult to reach hepatotoxic doses&#46; This fatal adverse reaction was observed using doses greater than 8&#8239;g&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and in some rare case of coexistence with autoimmune hepatitis&#44; in which a rebound phenomenon occurred after GC treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In this sense&#44; it is particularly important to warn about polypharmacy with other hepatotoxic drugs &#40;non-steroidal anti-inflammatory drugs&#44; statins&#44; etc&#46;&#41;&#44; as well as antithyroid drugs that&#44; in many cases&#44; are administered together&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In addition to the regimen recommended by EUGOGO there is another alternative regimen consisting of 3 pulses of 1&#8239;g of methylprednisolone monthly for 6 months with an efficacy similar to the standard regimen&#44; with no major side reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In cases of optic neuropathy in the active phase&#44; the use of 1&#8239;g during 3 consecutive days is recommended&#59; and if they respond&#44; repeat the regimen a week later&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The administration of GC locally through peribulbar injections has been shown to reduce the inflammatory signs of moderate GO&#44; with reductions in diplopia and muscle size&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> However&#44; there are studies that suggest little efficacy in the use of periocular injections&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Radiotherapy</span><p id="par0065" class="elsevierStylePara elsevierViewall">Local radiotherapy is considered as salvage therapy&#44; which can be useful in association with GC&#46; The most common dose is usually 2000&#8239;rads &#40;20&#8239;Gy&#41; in the retro-orbital area&#44; administered in 10 sessions of 200&#8239;rads &#40;2&#8239;Gy&#41; over 2 weeks&#46; A meta-analysis demonstrated its usefulness to improve symptoms such as diplopia and inflammatory involvement of the GO&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However&#44; there are studies that doubt its usefulness&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> Post-radiotherapy worsening has been described&#44; which would be controlled with low doses of GC and should not be interpreted as treatment failure&#46; In relation to the radiotherapy technique used&#44; there do not seem to be many differences between volumetric modulated therapy versus intensity-modulated radiation therapy&#44; although the latter seems to provide greater safety&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> In routine clinical practice&#44; the role of radiotherapy would be relegated to those patients with a lack of adequate response to corticosteroid therapy&#44; where this treatment associated with GC at lower doses &#40;half the dose of the Kahaly et al&#46; regimen&#41; could help to control symptoms&#46; Although it is generally safe and well tolerated&#44; there is a risk of causing retinopathy&#44; especially in diabetic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Mycophenolate</span><p id="par0070" class="elsevierStylePara elsevierViewall">Mycophenolate in its sodium or mofetil formulation has been used extensively in various systemic autoimmune diseases&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> despite the fact that it is only indicated to prevent rejection in solid organ transplantation&#46; Its ease of dosage &#40;oral&#41;&#44; together with its safety and good tolerance&#44; facilitate adherence to treatment&#46; Regarding GO treatment&#44; it has been used either exclusively<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> or in combination with GC&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> In this last scenario&#44; the <span class="elsevierStyleItalic">moderate-to-severe Graves&#39; orbitopathy</span> study demonstrated that the use of mycophenolate sodium at doses of 360&#8239;mg every 12&#8239;h&#44; together with intravenous GC&#44; obtained higher response rates at the end of the follow-up with a very adequate adverse reaction profile&#46; However&#44; relapse rates were similar in the 2 groups&#44; so its role as a second-line drug is unclear&#44; and further studies may need to be conducted to establish its definitive role&#46; Regarding monotherapy with mycophenolate&#44; a situation which may arise in those patients with GC intolerance&#44; we only have one study carried out in China&#44; where the outcomes were better compared to GC treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> However&#44; the study&#39;s methodology has been criticized for not performing adequate blinding&#46; In addition&#44; cases of optic neuropathy were detected in patients who had received mycophenolate&#44; which again requires further studies to reveal its true effectiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Rituximab</span><p id="par0075" class="elsevierStylePara elsevierViewall">It is a monoclonal antibody that blocks CD20&#44; which is expressed in the B lymphocyte&#46; Its fundamental use comes from experience in the haematology-oncology field&#44; where it revolutionized the treatment approach of many lymphoproliferative disorders&#44; as well as in the field of systemic autoimmune diseases&#46; Regarding GO&#44; it was speculated that its usefulness could be important&#44; given that it is a disease mediated by antibodies against the TSH receptor&#46; However&#44; it was observed that&#44; with B cell depletion treatment&#44; the levels of antibodies are not modified&#44; which suggests that the mode of action in this disease should involve T cell activity modulation&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> It was the first biological treatment used in GO&#44; after several case series&#44; which suggested an improved clinical activity score&#46; Two clinical trials were conducted&#44; the results of which were contradictory&#46; In one of them&#44; no differences were found in the clinical activity of the disease between treatment with rituximab &#40;total dose of 2&#8239;g&#41; and placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In contrast&#44; Salvi et al&#46; showed that rituximab &#40;at doses of 0&#46;5&#8239;g and 2&#8239;g&#41; had improved disease activity and led to greater inactivation of GO compared to high doses of intravenous GC &#40;7&#46;5&#8239;g&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> There has been much speculation about the reason for these 2 conflicting results&#46; In a <span class="elsevierStyleItalic">post hoc</span> analysis using the EUGOGO criteria&#44; the authors of both trials propose that the results were not significantly different&#46; They also attribute the different results to differences in the sample&#44; with younger patients&#44; with a shorter duration of the disease&#44; with lower levels of anti-TSH receptor antibodies in the European trial&#44; as well as differences in smoking habits&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> It is important to highlight that cases of dysthyroid optic neuropathy were observed in one of the studies&#44; and that one of them was related to the release of cytokines&#44; a condition which improved with the steroid treatment&#46; It seems that this treatment can work in those patients with active GO and if the course of the disease is short&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Currently the EUGOGO guidelines recommend rituximab in patients refractory to steroid treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Tocilizumab</span><p id="par0080" class="elsevierStylePara elsevierViewall">Tocilizumab is a monoclonal antibody that blocks the interleukin 6 &#40;IL-6&#41; receptor and is used as a biologic drug in the treatment of autoinflammatory diseases and systemic autoimmune diseases&#44; such as rheumatoid arthritis and giant cell arteritis&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> IL-6 is a ubiquitous protein in the body and highly involved in the control of the inflammatory response&#46; In GO&#44; it has a relevant role as an inducer of local inflammation in relation to the increase in the expression of the thyrotropin receptor in the orbital connective tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> After the favourable reaction and clinical progression of cases with active GO that responded to treatment with tocilizumab&#44; a randomized double-blind clinical trial with placebo was conducted in our country that demonstrated the improvement in activity in patients with GC-refractory GO<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#46; However&#44; no significant difference was found in exophthalmos reduction at week 40 compared to placebo&#46; The trial used doses of 8&#8239;mg&#47;kg&#44; monthly&#44; in intravenous formulation for 4 months&#46; There are&#44; however&#44; other studies where subcutaneous parenteral administration at doses of 162&#8239;mg for a total of 4 doses&#44; which can be given weekly &#40;if weight&#8239;&#62;&#8239;100&#8239;kg&#41; or every 15 days &#40;weight&#8239;&#60;&#8239;100&#8239;kg&#41;&#44; has demonstrated safety and efficacy in GO inflammation control&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Teprotumumab</span><p id="par0085" class="elsevierStylePara elsevierViewall">It is a humanized monoclonal antibody against the G1 immunoglobulin subclass&#46; It acts by binding to the insulin growth factor 1 &#40;IGF1R&#41; receptor&#44; acting as a powerful inhibitor of the activation of IGF1R signalling&#44; which is over-expressed in orbital fibroblasts and which plays a particularly important role in GO inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;43&#44;44</span></a> There are 2 clinical trials of teprotumumab for GO with very positive results compared to placebo&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46</span></a> which has prompted its approval by the <span class="elsevierStyleItalic">Food and Drug Administration</span> for the treatment of GO&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> In the former&#44; up to 69&#37; of patients in the drug group showed significant improvements in the clinical activity score&#46; Regarding safety&#44; the patients developed infectious and gastrointestinal events&#44; and there was one case of immune-mediated encephalopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> The second pivotal study was carried out in patients with recently diagnosed GO &#40;up to 9 months of previous symptoms&#41; and with data of moderate activity&#44; without prior treatment with GC&#46; Those who received teprotumumab had a response rate of 83&#37; compared to 10&#37; in the placebo group&#44; and practically all the secondary endpoints &#40;diplopia&#44; proptosis&#44; quality of life&#41; showed a clinically and statistically significant improvement&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Treatment consists of administering a first infusion of 10&#8239;mg&#47;kg followed by 7 infusions of 20&#8239;mg&#47;kg every 3 weeks&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Cyclosporine&#47;mTOR inhibitors</span><p id="par0095" class="elsevierStylePara elsevierViewall">The use of cyclosporine in GO began as a result of its inhibitory action on the T lymphocyte&#44; as it decreased the levels of IL-2&#46; Its use is based on former research when biological therapy did not exist&#46; However&#44; there is evidence that shows that the combination of cyclosporine at doses of 5&#8211;7&#46;5&#8239;mg&#47;kg with GC versus cyclosporine monotherapy shows superiority in terms of clinical activity&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Treatment with cyclosporine is usually reserved for cases refractory to GC&#44; radiotherapy&#44; or other biological therapy&#46; Its adverse reactions &#40;kidney toxicity&#44; high blood pressure&#44; risk of infections&#41; and the fact that it requires a long-term treatment greatly limit its use&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Other treatments for Graves&#39; ophthalmopathy</span><p id="par0105" class="elsevierStylePara elsevierViewall">Given their potential immunosuppressive effect&#44; treatments such as methotrexate&#44; azathioprine&#44; and intravenous immunoglobulins have been used with little clinical impact&#44; or with anecdotal benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Methotrexate has been analysed in retrospective studies in combination with GC with the intention of taking advantage of its GC-sparing effect&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> However&#44; its potential effect in patients without steroid treatment is unknown&#46; Intravenous immunoglobulins can be used in refractory situations&#44; when potent immunosuppressive treatments have been used and further immunosuppression is not desired&#44; since they have been shown to be effective in a similar way to GC&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Its cost and the need to maintain therapy for several months makes it necessary to limit this treatment to exceptional situations&#46; As in biological therapy with rituximab and teprotumumab&#44; anti-tumour necrosis factor treatments have previously been used &#9001; &#40;adalimumab&#44; etanercept and infliximab&#41; in isolated cases with not very robust results&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Role of surgery in Graves&#39; ophthalmopathy</span><p id="par0110" class="elsevierStylePara elsevierViewall">Surgery in GO is indicated in the acute phase to treat compressive optic neuropathy that does not respond to GC or corneal exposure refractory to conservative measures&#44; and in the inactive phase to treat any sequelae that produces an alteration in the quality of life and a candidate for surgical improvement&#46; Surgery in the inactive phase in cases of eyelid retraction or exophthalmos should not be considered cosmetic but rehabilitative surgery&#44; since patients do not try to gain beauty&#44; but to have their eyes as similar as possible to what they were before the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Surgery in GO has been shown to greatly improve the quality of life of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Rehabilitative surgery consists of one or more of the following procedures&#58; orbital decompression to correct the exophthalmos&#44; surgery of the extraocular muscles to correct strabismus&#44; and upper eyelid levator muscle or M&#252;ller&#39;s muscle weakening surgery to correct eyelid retraction&#46; Eyelid surgery may also require performing posterior lamina grafts to treat lower eyelid retraction&#44; or lipectomies to correct excess orbital fat and <span class="elsevierStyleItalic">retro-orbicularis oculi fat</span> &#40;ROOF&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Since the first description of the use of orbital decompression in GO&#44; multiple variants of the technique have been described&#46; Very few of these articles have sufficient scientific rigor to represent high-level clinical evidence&#44; so literature reviews can only summarize the techniques described&#44; and provide general concepts of efficacy and complications&#46; In general&#44; orbital decompression has good results in correcting the exophthalmos&#44; with a tolerable complication profile&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">With regard to strabismus surgery&#44; achieving a field of single binocular vision in the primary position and infraversion with a single surgical intervention is recommended&#46; As it is a restrictive strabismus&#44; it is recommended to perform weakening procedures&#44; mainly retro-insertions&#46; There are different nomograms and techniques to estimate which is the optimal weakening procedure&#44; but none has shown clear superiority over the others&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">For the correction of eyelid retraction&#44; as it happens with the other rehabilitative surgeries for GO&#44; there is no single common technique for all cases&#46; There are multiple techniques that act on M&#252;ller&#39;s muscle and&#47;or the levator muscle of the upper eyelid&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;54</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0135" class="elsevierStylePara elsevierViewall">GO is an autoimmune inflammatory disease that usually occurs in a single self-limiting exacerbation lasting a couple of years&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The active phase is treated medically&#44; and the drugs used depend on the severity of the disease&#46; Mild cases are treated with selenium and general measures&#46; Moderate-severe cases are treated first-line with intravenous GC&#46; In cases of resistance or recurrence&#44; the most widely used second-line treatments are radiotherapy and biological drugs such as teprotumumab&#44; tocilizumab or rituximab&#46; In vision-threatening cases&#44; GC treatment must be administered at high doses&#44; and salvage surgical orbital decompression is often required&#46; Smoking cessation is especially important to control disease activity&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The sequelae of GO in the inactive phase can be treated with surgery&#44; significantly improving the quality of life of patients&#46; Immunosuppressive treatment is not recommended in this phase&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interests</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest regarding the publication of this article&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Non-pharmacological measures&#46; Favourable and prognostic factors"
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              "titulo" => "Mycophenolate"
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            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Rituximab"
            ]
            4 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Tocilizumab"
            ]
            5 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Teprotumumab"
            ]
            6 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Cyclosporine&#47;mTOR inhibitors"
            ]
            7 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Other treatments for Graves&#39; ophthalmopathy"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Role of surgery in Graves&#39; ophthalmopathy"
        ]
        8 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conclusions"
        ]
        9 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conflict of interests"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-05-24"
    "fechaAceptado" => "2020-07-13"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1336334"
          "palabras" => array:7 [
            0 => "Graves-Basedow disease"
            1 => "Graves&#39; ophthalmopathy"
            2 => "Orbitopathy"
            3 => "Glucocorticoids"
            4 => "Teprotumumab"
            5 => "Rituximab"
            6 => "Tocilizumab"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1336335"
          "palabras" => array:7 [
            0 => "Enfermedad de Graves-Basedow"
            1 => "Inflamaci&#243;n orbitaria"
            2 => "Orbitopat&#237;a"
            3 => "Glucocorticoides"
            4 => "Teprotumumab"
            5 => "Rituximab"
            6 => "Tocilizumab"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Graves&#39; ophthalmopathy is an inflammatory disease with primary involvement of the extraocular muscles and the orbit&#46; It encompasses the most common extra-thyroid manifestation in patients with Graves-Basedow disease&#46; The underlying cause is molecular mimicry with the TSH receptor in ocular fibroblasts&#44; leading to an immuno-mediated pathogenesis&#46; Glucocorticoids at high doses are the cornerstone in moderate-severe cases&#46; However&#44; some patients are corticorresistant or intolerant&#46; In recent years&#44; therapeutic novelties have been described in terms of the dosage of the immunosuppressive treatments used&#44; as well as the emergence of biological therapy in this field&#46; The objective of this review is to update the treatment of Graves&#8217; ophthalmopathy&#44; as well as to present alternative options in patients resistant or intolerant to glucocorticoids&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La oftalmopat&#237;a de Graves constituye una enfermedad inflamatoria con afectaci&#243;n fundamental de los m&#250;sculos extraoculares y de la &#243;rbita&#44; y representa la principal manifestaci&#243;n extratiroidea en los pacientes con enfermedad de Graves-Basedow&#46; La etiopatogenia subyacente es inmunomediada mediante un mimetismo molecular con el receptor de la TSH en los fibroblastos oculares&#46; El principal tratamiento en los casos moderados-graves se basa en la inmunosupresi&#243;n sist&#233;mica&#44; y son de elecci&#243;n los glucocorticoides a dosis altas&#46; Sin embargo&#44; algunos pacientes presentan intolerancia al tratamiento o mala respuesta a los glucocorticoides&#46; En los &#250;ltimos a&#241;os se han descrito novedades terap&#233;uticas en cuanto a la posolog&#237;a de los tratamientos inmunosupresores empleados&#44; as&#237; como la irrupci&#243;n de la terapia biol&#243;gica en este campo&#46; El objetivo de esta revisi&#243;n es actualizar el tratamiento de la oftalmopat&#237;a inflamatoria&#44; as&#237; como presentar opciones terap&#233;uticas alternativas en aquellos casos corticoresistentes o con intolerancia a glucocorticoides&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as&#58; Gonz&#225;lez-Garc&#237;a A&#44; Sales-Sanz M&#46; Tratamiento de la oftalmopat&#237;a de Graves&#46; Med Clin &#40;Barc&#41;&#46; 2021&#59;156&#58;180&#8211;186&#46;</p>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:8 [
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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        "detalles" => array:1 [
          0 => array:3 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A&#58; Patient with mild active thyroid eye disease&#44; with slight right exophthalmos&#44; retraction of the upper right eyelid and minimal bilateral soft tissue oedema&#46; B&#58; the same patient in figure A after treatment with selenium&#46; Note the improvement in soft tissue oedema and the return to normality of the right upper eyelid retraction&#46; C&#58; Patient with active moderate-severe thyroid eye disease with exophthalmos and bilateral upper eyelid retraction&#44; and orbital inflammation with hyperaemia and eyelid and conjunctival oedema&#46; D&#58; the same patient in figure C 6 months after glucocorticoid bolus treatment&#46; The disease has been inactivated with disappearance of inflammatory signs and partial improvement in severity &#40;photographs shown with the consent of the patients&#41;&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1351
            "Ancho" => 900
            "Tamanyo" => 166962
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Patient with thyroid eye disease in active phase &#40;A&#41;&#46; Note chemosis and orbital oedema&#46; There is exophthalmos and strabismus&#46; B&#58; In the inactive phase after treatment with glucocorticoid boluses and tocilizumab&#46; The disease is inactive&#44; but fibrosis sequelae persist&#46; C&#58; After rehabilitative surgery with orbital decompression&#44; strabismus surgery and eyelid retraction surgery&#46; It largely succeeds in restoring the patient&#39;s pre-disease normal appearance &#40;photographs shown with the consent of the patient&#41;&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0015"
            "detalle" => "Table "
            "rol" => "short"
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        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">DON&#58; Dysthyroid Optic Neuropathy&#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="\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">Forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics and recommendations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Those that do not alter quality of life sufficiently to justify treatment with systemic glucocorticoids</span>Eyelid retraction under 2&#8239;mmMild soft tissue involvementExophthalmos under 3&#8239;mmMinimal corneal involvement that responds to lubricantsA mild transient diplopiaFavourable progression with <span class="elsevierStyleItalic">watchful waiting</span>Local measures with topical lubricants&#47;ocular occlusion during night rest<span class="elsevierStyleItalic">Selenium</span> &#40;100&#8239;mg every 12&#8239;h for 6 months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate-severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">These forms are those that do not exhibit any signs of risk to vision and that the quality of life is affected to the point of requiring <span class="elsevierStyleItalic">immunosuppressive</span> therapy to control the inflammatory processGlucocorticoid pulses &#40;Kahaly&#39;s regimen&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DON&#46; Optic nerve involvement</span>Decreased visual acuityMarcus Gunn pupilColour vision deficiencyPapilledemaVisual field defectsApical crowding on the radiographic image<span class="elsevierStyleItalic">Methylprednisolone pulses 500&#8722;1&#44;000&#8239;mg daily for 3 days followed by decompressive surgery</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2524042.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Kahaly&#39;s regimen&#58; 500&#8239;mg of intravenous methylprednisolone weekly for 6 weeks&#44; and subsequently 250&#8239;mg of intravenous methylprednisolone weekly for an additional 6 weeks&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Classification and treatment recommendations in Graves&#39; ophthalmopathy&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0020"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">HbA1c&#58; glycated haemoglobin&#59; IgA&#58; immunoglobulin A&#59; IgG&#58; immunoglobulin G&#59; IgM&#58; immunoglobulin M&#59; iv&#58; intravenous&#59; sc&#58; subcutaneous&#59; HBV&#58; hepatitis B virus&#59; HCV&#58; hepatitis C virus&#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="\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">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pre-screening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Monitoring&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glucocorticoids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HbA1c&#44; Glucose&#44; liver profileHBV&#44; HCV serologiesScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">500&#8239;mg iv <span class="elsevierStyleItalic">&#40;first 6 weeks&#41;</span>250&#8239;mg iv <span class="elsevierStyleItalic">&#40;next 6 weeks&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liver profile at 1&#8722;2 months and after the end of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mycophenolate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete blood count&#44; liver profileHBV&#44; HCV serologiesScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">360&#8239;mg <span class="elsevierStyleItalic">every</span> 12&#8239;h<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> orally OR 1&#8239;g <span class="elsevierStyleItalic">every 12</span>&#8239;<span class="elsevierStyleItalic">hours</span><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a> orally <span class="elsevierStyleItalic">24 weeks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete blood count and liver profile every 6&#8722;8 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rituximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HBV&#44; HCV serologiesIgG&#44; IgA&#44; IgM immunoglobulinsScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 doses of 1&#8239;g spread over 14 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete blood count &#40;per month&#41;IgG&#44; IgA&#44; IgM immunoglobulins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tocilizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liver profileComplete blood countHBV&#44; HCV serologiesScreening for latent tuberculosis infection<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 mg&#47;kg <span class="elsevierStyleItalic">monthly &#40;4 months</span><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">d</span></a><span class="elsevierStyleItalic">&#41; iv or</span> 162&#8239;mg weekly&#47;biweekly sc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipoprotein electrophoresisLiver profileComplete blood count&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Teprotumumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HbA1c&#44; blood glucoseKidney function&#44; liver profileComplete blood countHBV&#44; HCV serologies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Every 3 weeks</span>20&#8239;mg&#47;kg <span class="elsevierStyleItalic">first dose iv&#46;</span> Subsequently 10&#8239;mg&#47;kg iv <span class="elsevierStyleItalic">up to a total of 8</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GlucoseLiver profile&#44; blood count&nbsp;\t\t\t\t\t\t\n
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Understanding the immunology of Graves&#8217; ophthalmopathy&#46; Is it an autoimmune disease&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;S&#46; Bahn"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1016/s0889-8529(05)70132-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinol Metab Clin North Am"
                        "fecha" => "2000"
                        "volumen" => "29"
                        "paginaInicial" => "287"
                        "paginaFinal" => "296"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10874530"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Advances in treatment of active&#44; moderate-to-severe Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "W&#46;M&#46; Wiersinga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-8587(16)30046-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Diabetes Endocrinol"
                        "fecha" => "2017"
                        "volumen" => "5"
                        "paginaInicial" => "134"
                        "paginaFinal" => "142"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27346786"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;S&#46; Bahn"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra0905750"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2010"
                        "volumen" => "362"
                        "paginaInicial" => "726"
                        "paginaFinal" => "738"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20181974"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Graves&#8217; ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels&#58; prevalence&#44; natural history&#44; and thyrotropin receptor antibody levels"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;H&#46; Khoo"
                            1 => "P&#46;H&#46; Eng"
                            2 => "S&#46;C&#46; Ho"
                            3 => "E&#46;S&#46; Tai"
                            4 => "N&#46;G&#46; Morgenthaler"
                            5 => "L&#46;L&#46; Seah"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/thy.2000.10.1093"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thyroid"
                        "fecha" => "2000"
                        "volumen" => "10"
                        "paginaInicial" => "1093"
                        "paginaFinal" => "1100"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11201855"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic factors in Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Frecker"
                            1 => "V&#46; Stenszky"
                            2 => "C&#46; Balazs"
                            3 => "L&#46; Kozma"
                            4 => "E&#46; Kraszits"
                            5 => "N&#46;R&#46; Farid"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Endocrinol &#40;Oxf&#41;"
                        "fecha" => "1986"
                        "volumen" => "25"
                        "paginaInicial" => "479"
                        "paginaFinal" => "485"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quality of life in Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "W&#46;M&#46; Wiersinga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Best Pract Res Clin Endocrinol Metab"
                        "fecha" => "2012"
                        "volumen" => "26"
                        "paginaInicial" => "359"
                        "paginaFinal" => "370"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Effect of abnormal thyroid function on the severity of Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;F&#46; Prummel"
                            1 => "W&#46;M&#46; Wiersinga"
                            2 => "M&#46;P&#46; Mourits"
                            3 => "L&#46; Koornneef"
                            4 => "A&#46; Berghout"
                            5 => "R&#46; van der Gaag"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1990"
                        "volumen" => "150"
                        "paginaInicial" => "1098"
                        "paginaFinal" => "1101"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1691908"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County&#44; Minnesota"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46;B&#46; Bartley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Trans Am Ophthalmol Soc"
                        "fecha" => "1994"
                        "volumen" => "92"
                        "paginaInicial" => "477"
                        "paginaFinal" => "588"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7886878"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smoking and thyroid disorders&#8211;a meta-analysis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Vestergaard"
                          ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/eje.0.1460153"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Endocrinol"
                        "fecha" => "2002"
                        "volumen" => "146"
                        "paginaInicial" => "153"
                        "paginaFinal" => "161"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11834423"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effectiveness of oral counselling for smoke cessation in Graves orbitopathy patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "P&#46; de-Arriba-Palomero"
                            1 => "M&#46; Sales-Sanz"
                            2 => "E&#46; Fuentemilla"
                            3 => "H&#46;R&#46; Won-Kim"
                            4 => "F&#46; de-Arriba-Palomero"
                            5 => "F&#46;J&#46; Mu&#241;oz-Negrete"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.oftal.2019.03.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Soc Esp Oftalmol"
                        "fecha" => "2019"
                        "volumen" => "94"
                        "paginaInicial" => "323"
                        "paginaFinal" => "330"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31036428"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Medical Treatment of Graves&#8217; Orbitopathy"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Salvi"
                            1 => "I&#46; Campi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0035-1554721"
                      "Revista" => array:6 [
                        "tituloSerie" => "Horm Metab Res"
                        "fecha" => "2015"
                        "volumen" => "47"
                        "paginaInicial" => "779"
                        "paginaFinal" => "788"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26361263"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The course of Graves&#8217; ophthalmopathy is not influenced by near total thyroidectomy&#58; a case-control study"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Marcocci"
                            1 => "G&#46; Bruno-Bossio"
                            2 => "L&#46; Manetti"
                            3 => "M&#46;L&#46; Tanda"
                            4 => "P&#46; Miccoli"
                            5 => "P&#46; Iacconi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Endocrinol &#40;Oxf&#41;"
                        "fecha" => "1999"
                        "volumen" => "51"
                        "paginaInicial" => "503"
                        "paginaFinal" => "508"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Radioiodine therapy &#40;RAI&#41; for Graves&#8217; disease &#40;GD&#41; and the effect on ophthalmopathy&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46;H&#46; Acharya"
                            1 => "A&#46; Avenell"
                            2 => "S&#46; Philip"
                            3 => "J&#46; Burr"
                            4 => "J&#46;S&#46; Bevan"
                            5 => "P&#46; Abraham"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Endocrinol &#40;Oxf&#41;"
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                        "volumen" => "69"
                        "paginaInicial" => "943"
                        "paginaFinal" => "950"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Occurrence of ophthalmopathy after treatment for Graves&#8217; hyperthyroidism&#46; The Thyroid Study Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Tallstedt"
                            1 => "G&#46; Lundell"
                            2 => "O&#46; Torring"
                            3 => "G&#46; Wallin"
                            4 => "J&#46;G&#46; Ljunggren"
                            5 => "H&#46; Blomgren"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199206253262603"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1992"
                        "volumen" => "326"
                        "paginaInicial" => "1733"
                        "paginaFinal" => "1738"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1489388"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent graves&#8217; orbitopathy&#58; a retrospective cohort study"
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                        0 => array:2 [
                          "etal" => true
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                            4 => "P&#46; Sivelli"
                            5 => "E&#46; Piantanida"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2009-2130"
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                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2010"
                        "volumen" => "95"
                        "paginaInicial" => "1333"
                        "paginaFinal" => "1337"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20061414"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Relation between therapy options for Graves&#8217; disease and the course of Graves&#8217; ophthalmopathy&#58; a systematic review and meta-analysis"
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                        0 => array:2 [
                          "etal" => false
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                            2 => "W&#46;K&#46; Hu"
                            3 => "X&#46;L&#46; Jiao"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40618-016-0484-y"
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                        "tituloSerie" => "J Endocrinol Invest"
                        "fecha" => "2016"
                        "volumen" => "39"
                        "paginaInicial" => "1225"
                        "paginaFinal" => "1233"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27220843"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0085"
              "etiqueta" => "17"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Randomized&#44; single blind trial of intravenous versus oral steroid monotherapy in Graves&#8217; orbitopathy"
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                            3 => "M&#46; Dittmar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2005-0148"
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                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2005"
                        "volumen" => "90"
                        "paginaInicial" => "5234"
                        "paginaFinal" => "5240"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15998777"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High-dose intravenous corticosteroid therapy for Graves&#8217; ophthalmopathy"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "P&#46;E&#46; Macchia"
                            1 => "M&#46; Bagattini"
                            2 => "G&#46; Lupoli"
                            3 => "M&#46; Vitale"
                            4 => "G&#46; Vitale"
                            5 => "G&#46; Fenzi"
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                    0 => array:2 [
                      "doi" => "10.1007/BF03343835"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Endocrinol Invest"
                        "fecha" => "2001"
                        "volumen" => "24"
                        "paginaInicial" => "152"
                        "paginaFinal" => "158"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11314743"
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              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Treatment modalities for Graves&#8217; ophthalmopathy&#58; systematic review and metaanalysis"
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                          "etal" => false
                          "autores" => array:6 [
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                            1 => "E&#46; Robenshtok"
                            2 => "M&#46; Hasanreisoglu"
                            3 => "D&#46; Ezrachi"
                            4 => "I&#46; Shimon"
                            5 => "L&#46; Leibovici"
                          ]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2009-0376"
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                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2009"
                        "volumen" => "94"
                        "paginaInicial" => "2708"
                        "paginaFinal" => "2716"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19491222"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0100"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves&#8217; orbitopathy"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Bartalena"
                            1 => "G&#46;E&#46; Krassas"
                            2 => "W&#46; Wiersinga"
                            3 => "C&#46; Marcocci"
                            4 => "M&#46; Salvi"
                            5 => "C&#46; Daumerie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2012-2389"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2012"
                        "volumen" => "97"
                        "paginaInicial" => "4454"
                        "paginaFinal" => "4463"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23038682"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0105"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Acute liver damage following intravenous glucocorticoid treatment for Graves&#8217; ophthalmopathy"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Moleti"
                            1 => "G&#46; Giuffrida"
                            2 => "G&#46; Sturniolo"
                            3 => "G&#46; Squadrito"
                            4 => "A&#46; Campenn&#236;"
                            5 => "S&#46; Morelli"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12020-016-0928-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrine"
                        "fecha" => "2016"
                        "volumen" => "54"
                        "paginaInicial" => "259"
                        "paginaFinal" => "268"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27003434"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0110"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves&#8217; ophthalmopathy"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Marino"
                            1 => "E&#46; Morabito"
                            2 => "M&#46;R&#46; Brunetto"
                            3 => "L&#46; Bartalena"
                            4 => "A&#46; Pinchera"
                            5 => "C&#46; Marocci"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/105072504774193276"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thyroid"
                        "fecha" => "2004"
                        "volumen" => "14"
                        "paginaInicial" => "403"
                        "paginaFinal" => "406"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15186621"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0115"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy and safety of pulsed intravenous methylprednisolone in early active thyroid eye disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;M&#46; Young"
                            1 => "A&#46;Y&#46;N&#46; Lim"
                            2 => "S&#46;S&#46; Lang"
                            3 => "K&#46;O&#46; Lee"
                            4 => "G&#46; Sundar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/01676830.2018.1553189"
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                        "tituloSerie" => "Orbit"
                        "fecha" => "2019"
                        "volumen" => "38"
                        "paginaInicial" => "362"
                        "paginaFinal" => "369"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30540214"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The 2016 European Thyroid Association&#47;European Group on Graves&#8217; Orbitopathy Guidelines for the Management of Graves&#8217; Orbitopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Bartalena"
                            1 => "L&#46; Baldeschi"
                            2 => "K&#46; Boboridis"
                            3 => "A&#46; Eckstein"
                            4 => "G&#46;J&#46; Kahaly"
                            5 => "C&#46; Marcocci"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000443828"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Thyroid J"
                        "fecha" => "2016"
                        "volumen" => "5"
                        "paginaInicial" => "9"
                        "paginaFinal" => "26"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27099835"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0125"
              "etiqueta" => "25"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Repeated peribulbar injections of triamcinolone acetonide&#58; a successful and safe treatment for moderate to severe Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46; Bordaberry"
                            1 => "D&#46;L&#46; Marques"
                            2 => "J&#46;C&#46; Pereira-Lima"
                            3 => "I&#46;M&#46; Marcon"
                            4 => "H&#46; Schmid"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1755-3768.2008.01171.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Ophthalmol"
                        "fecha" => "2009"
                        "volumen" => "87"
                        "paginaInicial" => "58"
                        "paginaFinal" => "64"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18937809"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0130"
              "etiqueta" => "26"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Orbital steroid injections"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;A&#46; Goldberg"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bjo.2004.051755"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Ophthalmol"
                        "fecha" => "2004"
                        "volumen" => "88"
                        "paginaInicial" => "1359"
                        "paginaFinal" => "1360"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15489472"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Radiotherapy for Graves&#8217; orbitopathy&#58; randomised placebo-controlled study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;P&#46; Mourits"
                            1 => "M&#46;L&#46; van Kempen-Harteveld"
                            2 => "M&#46;B&#46; Garcia"
                            3 => "H&#46;P&#46; Koppeschaar"
                            4 => "L&#46; Tick"
                            5 => "C&#46;B&#46; Terwee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2000"
                        "volumen" => "355"
                        "paginaInicial" => "1505"
                        "paginaFinal" => "1509"
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0140"
              "etiqueta" => "28"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A prospective&#44; randomized&#44; double-blind&#44; placebo-controlled study of orbital radiotherapy for Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;A&#46; Gorman"
                            1 => "J&#46;A&#46; Garrity"
                            2 => "V&#46; Fatourechi"
                            3 => "R&#46;S&#46; Bahn"
                            4 => "I&#46;A&#46; Petersen"
                            5 => "S&#46;L&#46; Stafford"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ophthalmology"
                        "fecha" => "2001"
                        "volumen" => "108"
                        "paginaInicial" => "1523"
                        "paginaFinal" => "1534"
                      ]
                    ]
                  ]
                ]
              ]
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            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of IMRT and VMAT radiotherapy planning for Graves&#8217; ophthalmopathy based on dosimetric parameters analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;C&#46; Wang"
                            1 => "J&#46; Wu"
                            2 => "X&#46;Q&#46; Xie"
                            3 => "X&#46;L&#46; Liu"
                            4 => "Y&#46; Luo"
                            5 => "F&#46; Wang"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.26355/eurrev_202004_20856"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Rev Med Pharmacol Sci"
                        "fecha" => "2020"
                        "volumen" => "24"
                        "paginaInicial" => "3898"
                        "paginaFinal" => "3906"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32329865"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term safety of orbital radiotherapy for Graves&#8217; ophthalmopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Marcocci"
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                            3 => "M&#46; Marin&#242;"
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                            5 => "E&#46; Morabito"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2003-030260"
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                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2003"
                        "volumen" => "88"
                        "paginaInicial" => "3561"
                        "paginaFinal" => "3566"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12915636"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
              ]
            ]
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              "identificador" => "bib0155"
              "etiqueta" => "31"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mycophenolate mofetil&#44; azathioprine and tacrolimus&#58; mechanisms in rheumatology"
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                          "etal" => false
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41584-020-0374-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol"
                        "fecha" => "2020"
                        "volumen" => "16"
                        "paginaInicial" => "167"
                        "paginaFinal" => "178"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32055040"
                            "web" => "Medline"
                          ]
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                  ]
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              ]
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              "identificador" => "bib0160"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves&#8217; orbitopathy"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            3 => "H&#46; Cui"
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                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Endocrinol &#40;Oxf&#41;"
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                        "volumen" => "86"
                        "paginaInicial" => "247"
                        "paginaFinal" => "255"
                      ]
                    ]
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              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mycophenolate plus methylprednisolone versus methylprednisolone alone in active&#44; moderate-to-severe Graves&#8217; orbitopathy &#40;MINGO&#41;&#58; a randomised&#44; observer-masked&#44; multicentre trial"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            2 => "J&#46; Konig"
                            3 => "S&#46; Pitz"
                            4 => "K&#46; Ponto"
                            5 => "T&#46; Diana"
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                        ]
                      ]
                    ]
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                        "tituloSerie" => "Lancet Diabetes Endocrinol"
                        "fecha" => "2018"
                        "volumen" => "6"
                        "paginaInicial" => "287"
                        "paginaFinal" => "298"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29396246"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Prospective&#44; systematically recorded mycophenolate safety data in Graves&#8217; orbitopathy"
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                          "etal" => false
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                            3 => "E&#46; Kolbe"
                            4 => "G&#46;J&#46; Kahaly"
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                        ]
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1007/s40618-016-0441-9"
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                        "tituloSerie" => "J Endocrinol Invest"
                        "fecha" => "2016"
                        "volumen" => "39"
                        "paginaInicial" => "687"
                        "paginaFinal" => "694"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26886940"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "B cells in Graves&#8217; Orbitopathy&#58; more than just a source of antibodies&#63;"
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                        0 => array:2 [
                          "etal" => false
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Eye &#40;Lond&#41;"
                        "fecha" => "2019"
                        "volumen" => "33"
                        "paginaInicial" => "230"
                        "paginaFinal" => "234"
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                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Randomized controlled trial of rituximab in patients with Graves&#8217; orbitopathy"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
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                            3 => "T&#46; Prabin"
                            4 => "E&#46;A&#46; Bradley"
                            5 => "R&#46;S&#46; Bahn"
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                    0 => array:2 [
                      "doi" => "10.1210/jc.2014-2572"
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                        "tituloSerie" => "J Clin Endocrinol Metab"
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                        "volumen" => "100"
                        "paginaInicial" => "432"
                        "paginaFinal" => "441"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25343233"
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                      "titulo" => "Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves&#8217; orbitopathy&#58; a randomized controlled study"
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                        0 => array:2 [
                          "etal" => true
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                            4 => "D&#46; Covelli"
                            5 => "D&#46; Dazzi"
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                    0 => array:2 [
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                        "paginaFinal" => "431"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25494967"
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                    0 => array:2 [
                      "titulo" => "MANAGEMENT OF ENDOCRINE DISEASE&#58; Rituximab therapy for Graves&#8217; orbitopathy - lessons from randomized control trials"
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                          "etal" => false
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                            0 => "M&#46;N&#46; Stan"
                            1 => "M&#46; Salvi"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/EJE-16-0552"
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                        "tituloSerie" => "Eur J Endocrinol"
                        "fecha" => "2017"
                        "volumen" => "176"
                        "paginaInicial" => "R101"
                        "paginaFinal" => "R109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27760790"
                            "web" => "Medline"
                          ]
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                    0 => array:2 [
                      "titulo" => "A review of recent advances using tocilizumab in the treatment of rheumatic diseases"
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                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46; Rubbert-Roth"
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                            2 => "J&#46;M&#46; Nebesky"
                            3 => "A&#46; Jin"
                            4 => "E&#46; Berber"
                          ]
                        ]
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                    ]
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                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatol Ther"
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                        "volumen" => "5"
                        "paginaInicial" => "21"
                        "paginaFinal" => "42"
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                    ]
                  ]
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            39 => array:3 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves&#8217; ophthalmopathy"
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                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;C&#46; Jyonouchi"
                            1 => "R&#46;W&#46; Valyasevi"
                            2 => "D&#46;A&#46; Harteneck"
                            3 => "C&#46;M&#46; Dutton"
                            4 => "R&#46;S&#46; Bahn"
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                        "tituloSerie" => "Thyroid"
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                        "volumen" => "11"
                        "paginaInicial" => "929"
                        "paginaFinal" => "934"
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                    ]
                  ]
                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves Orbitopathy&#58; A randomized clinical trial"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;V&#46; Perez-Moreiras"
                            1 => "J&#46;J&#46; Gomez-Reino"
                            2 => "J&#46;R&#46; Maneiro"
                            3 => "E&#46; Perez-Pampin"
                            4 => "A&#46; Romo Lopez"
                            5 => "F&#46;M&#46; Rodr&#237;guez Alvarez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Ophthalmol"
                        "fecha" => "2018"
                        "volumen" => "195"
                        "paginaInicial" => "181"
                        "paginaFinal" => "190"
                      ]
                    ]
                  ]
                ]
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            41 => array:3 [
              "identificador" => "bib0210"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Subcutaneous Tocilizumab for Thyroid Eye Disease&#58; Simplified Dosing and Delivery"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
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                            1 => "O&#46;O&#46; Idowu"
                            2 => "R&#46;C&#46; Kersten"
                            3 => "M&#46;R&#46; Vagefi"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ophthalmic Plast Reconstr Surg"
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                        "volumen" => "35"
                        "paginaInicial" => "e64"
                        "paginaFinal" => "e66"
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                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0215"
              "etiqueta" => "43"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New insights into the pathogenesis and nonsurgical management of Graves orbitopathy"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;N&#46; Taylor"
                            1 => "L&#46; Zhang"
                            2 => "R&#46;W&#46;J&#46; Lee"
                            3 => "I&#46; Muller"
                            4 => "D&#46;G&#46; Ezra"
                            5 => "C&#46;M&#46; Dayan"
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                    0 => array:2 [
                      "doi" => "10.1038/s41574-019-0305-4"
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                        "tituloSerie" => "Nat Rev Endocrinol"
                        "fecha" => "2020"
                        "volumen" => "16"
                        "paginaInicial" => "104"
                        "paginaFinal" => "116"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31889140"
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                  ]
                ]
              ]
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              "identificador" => "bib0220"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy"
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                          "etal" => false
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocr Rev"
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                        "paginaInicial" => "236"
                        "paginaFinal" => "267"
                      ]
                    ]
                  ]
                ]
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            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "45"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Teprotumumab for Thyroid-Associated Ophthalmopathy"
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                          "etal" => true
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                            0 => "T&#46;J&#46; Smith"
                            1 => "G&#46;J&#46; Kahaly"
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                            3 => "J&#46;C&#46; Fleming"
                            4 => "R&#46;A&#46; Dailey"
                            5 => "R&#46;A&#46; Tang"
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                        "tituloSerie" => "N Engl J Med"
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                        "paginaInicial" => "1748"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28467880"
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                          ]
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Teprotumumab for the Treatment of Active Thyroid Eye Disease"
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                          "etal" => true
                          "autores" => array:6 [
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                            3 => "S&#46; Sile"
                            4 => "E&#46;H&#46;Z&#46; Thompson"
                            5 => "R&#46; Perdok"
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                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1910434"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2020"
                        "volumen" => "382"
                        "paginaInicial" => "341"
                        "paginaFinal" => "352"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31971679"
                            "web" => "Medline"
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                  ]
                ]
              ]
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            46 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "47"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Teprotumumab&#58; First Approval"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46; Markham"
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                      "Revista" => array:5 [
                        "tituloSerie" => "Drugs"
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                        "paginaInicial" => "509"
                        "paginaFinal" => "512"
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                    ]
                  ]
                ]
              ]
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            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ciclosporin and prednisone v&#46; prednisone in treatment of Graves&#8217; ophthalmopathy&#58; a controlled&#44; randomized and prospective study"
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                        0 => array:2 [
                          "etal" => true
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                            3 => "B&#46; Schweikert"
                            4 => "S&#46; Meuer"
                            5 => "W&#46; Muller"
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                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2362.1986.tb01016.x"
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                        "tituloSerie" => "Eur J Clin Invest"
                        "fecha" => "1986"
                        "volumen" => "16"
                        "paginaInicial" => "415"
                        "paginaFinal" => "422"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3100309"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
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                    0 => array:2 [
                      "titulo" => "Methotrexate as an Adjuvant in Severe Thyroid Eye Disease&#58; Does It Really Work as a Steroid-Sparing Agent&#63;"
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                          "etal" => true
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                            3 => "S&#46; Lang"
                            4 => "M&#46; Yang"
                            5 => "A&#46; Looi"
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                        "volumen" => "35"
                        "paginaInicial" => "369"
                        "paginaFinal" => "373"
                        "link" => array:1 [
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                    0 => array:2 [
                      "titulo" => "Current and Emerging Treatment Strategies for Graves&#8217; Orbitopathy"
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                        "volumen" => "79"
                        "paginaInicial" => "109"
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                ]
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                    0 => array:2 [
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Orbit"
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                        "volumen" => "35"
                        "paginaInicial" => "121"
                        "paginaFinal" => "125"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27159575"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Orbital decompression for thyroid eye disease"
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                        "tituloSerie" => "Surv Ophthalmol"
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                        "paginaInicial" => "86"
                        "paginaFinal" => "104"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28343872"
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                    0 => array:2 [
                      "titulo" => "Clinical Pearls and Management Recommendations for Strabismus due to Thyroid Orbitopathy"
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                        "tituloSerie" => "Middle East Afr J Ophthalmol"
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                        "link" => array:1 [
                          0 => array:2 [
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                    0 => array:2 [
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