Reasons to consider low-dose of methimazole as the best option to treat patients with recurrent Graves’ hyperthyroidism

García-Mayor, R.V.

doi:10.1016/j.rceng.2019.01.006

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García-Mayor" "autores" => array:1 [ 0 => array:4 [ "nombre" => "R.V." "apellidos" => "García-Mayor" "email" => array:2 [ 0 => "ricardo.garcia.mayor@sergas.es" 1 => "garcia-mayor@uvigo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Endocrinología, Hospital HM Vigo, Vigo, Pontevedra, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Investigación Sanitaria Galicia Sur, Vigo, Pontevedra, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Razones por las que considerar a las dosis bajas de metimazol como la mejor opción para tratar a los pacientes con hipertiroidismo de Graves recurrente" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2214 "Ancho" => 2917 "Tamanyo" => 536526 ] ] "descripcion" => array:1 [ "en" => "Advantages and disadvantages of the 3 therapeutic modalities for treating patients with recurrent Graves’ hyperthyroidism. Abbreviations: MMI: methimazole; RAI: radioactive iodine; TT: total thyroidectomy." ] ] ] "textoCompleto" => "Graves’ hyperthyroidism (GH) is the most common form of hyperthyroidism in populations with an adequate iodine intake, which, despite incidence peaks between 30 and 50 years of age, can affect individuals of any age. Untreated GH is associated with increased mortality and morbidity; timely treatment of GH is therefore critical.The therapeutic options for patients with GH include antithyroid drugs (ATDs), such as methimazole, carbimazole and propylthiouracil, whose purpose is to recover euthyroidism while the autoimmune process resolves. The options also include radioactive iodine (RAI) therapy and total thyroidectomy (TT), whose purpose is to induce permanent hypothyroidism followed by thyroid hormone replacement. Although each of these options has been shown effective, all have a number of drawbacks. Currently, the first option for treating newly diagnosed cases of GH is administering ATDs.<a class="elsevierStyleCrossRef" href="#bib0080">1</a> However, there is no consensus on the optimal therapy for patients with recurrent GH. The discussion between physician and patient as to the best therapeutic option should consider the following aspects, as recommended by the main therapeutic protocols<a class="elsevierStyleCrossRef" href="#bib0085">2</a>:The natural course of GH: As happens with other autoimmune diseases, GH activity can oscillate over the course of the disease; patients can enter a remission phase without undergoing any type of specific treatment.<a class="elsevierStyleCrossRef" href="#bib0090">3</a>GH that transforms into Hashimoto's thyroiditis: Although Graves’ disease and Hashimoto's thyroiditis were initially considered 2 separate processes, they are now considered different manifestations of the same disease. It is well known that the natural course of GH can result in hypothyroidism in 10–20% of patients.<a class="elsevierStyleCrossRef" href="#bib0095">4</a>Long-term thionamide-induced remission of GH: The evidence on this finding shows that treatment with ATDs is usually accompanied by GH remission beyond the disease's natural history. In terms of the underlying mechanism, it is unclear whether this remission is due to the immunomodulatory effect of ATDs or is associated with the euthyroidism induced by these drugs.<a class="elsevierStyleCrossRef" href="#bib0100">5</a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">–Risk factors that predict a GH relapse after interrupting ATD therapy: The following factors are associated with a greater risk of relapse after withdrawing ATDs: young age, male sex, tobacco use, large goiter, biochemistry indicating severe GH, high levels of thyroid-stimulating immunoglobulins and, more recently, some genetic markers. However, none of these parameters has been shown to be useful for determining patients’ individual prognoses.<a class="elsevierStyleCrossRef" href="#bib0105">6</a></li><li class="elsevierStyleListItem" id="lsti0010">–The response of patients with recurrent GH to other ATD cycles: Generally, physicians believe that patients with recurrent GH do not usually respond effectively to new ATD cycles, which leads them to choose RAI for these cases. However, previous and recent studies have demonstrated that a second ATD cycle in patients with recurrent GH leads to satisfactory long-term remission.<a class="elsevierStyleCrossRef" href="#bib0110">7</a></li><li class="elsevierStyleListItem" id="lsti0015">–The objective of RAI therapy and TT is to reduce the functional mass of the thyroid tissue, which results in athyreotic hypothyroidism (AH) whose management is complicated.<a class="elsevierStyleCrossRef" href="#bib0115">8</a> Thyroid function should be monitored after ablation and the AH treated for life.</li><li class="elsevierStyleListItem" id="lsti0020">–The 3 therapeutic options are associated with problems and complications: The main problem with ATD therapy is relapses, which occur in approximately 50% of patients who discontinue the drug. Given that the objective of RAI and TT is for the patient to develop hypothyroidism, we cannot consider athyreotic hypothyroidism as a complication. The main problem with RAI therapy is related to the progression of Graves’ ophthalmopathy, especially in patients who smoke and those with active ocular disease. The safety and efficacy of TT is highly dependent on the surgeon's skill and experience. RAI is related to increased morbidity and mortality due to cardiovascular disease.<a class="elsevierStyleCrossRef" href="#bib0120">9</a> The clinical factors favoring TT are the large goiter with compression symptoms, concurrent thyroid nodules suspected of malignancy and worsening ophthalmopathy. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> lists the complications associated with each treatment.<a class="elsevierStyleCrossRefs" href="#bib0125">10–12</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0025">–Long-term studies have shown the advantages of GH therapy with methimazole overRAI<a class="elsevierStyleCrossRef" href="#bib0140">13</a>: A systematic review and recent meta-analysis confirmed that long-term ADT therapy (>24 months) is safe and effective, although mainly in adults.<a class="elsevierStyleCrossRef" href="#bib0145">14</a> Another study compared the efficacy and long-term safety of therapy with low-dose methimazole (initial dose of 10–20mg and maintenance dose of 2.5–7.5mg) compared with RAI therapy in patients with GH relapse. In this article, the authors observed that in the low-dose methimazole group, the rate of euthyroidism was higher than in the RAI group. In contrast, the rate of manifest and subclinical hypothyroidism was higher in the RAI group. As has been previously observed, RAI therapy was associated with a lack of improvement or worsening of Graves’ ophthalmopathy. None of the patients in the methimazole group developed relevant adverse effects. RAI therapy was also associated with weight gain, especially after 24 months of follow-up, which is probably because the number of patients with subclinical and manifest hypothyroidism in this group was larger.<a class="elsevierStyleCrossRef" href="#bib0150">15</a></li></ul>In conclusion and considering the above, extended low-dose metamizole is the best option for treating patients with recurrent GH in standard practice." 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all have a number of drawbacks&#46; Currently&#44; the first option for treating newly diagnosed cases of GH is administering ATDs&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> However&#44; there is no consensus on the optimal therapy for patients with recurrent GH&#46; The discussion between physician and patient as to the best therapeutic option should consider the following aspects&#44; as recommended by the main therapeutic protocols<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a>&#58;</p><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The natural course of GH</span>&#58; As happens with other autoimmune diseases&#44; GH activity can oscillate over the course of the disease&#59; patients can enter a remission phase without undergoing any type of specific treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">GH that transforms into Hashimoto&#39;s thyroiditis</span>&#58; Although Graves&#8217; disease and Hashimoto&#39;s thyroiditis were initially considered 2 separate processes&#44; they are now considered different manifestations of the same disease&#46; It is well known that the natural course of GH can result in hypothyroidism in 10&#8211;20&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Long-term thionamide-induced remission of GH</span>&#58; The evidence on this finding shows that treatment with ATDs is usually accompanied by GH remission beyond the disease&#39;s natural history&#46; In terms of the underlying mechanism&#44; it is unclear whether this remission is due to the immunomodulatory effect of ATDs or is associated with the euthyroidism induced by these drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8211;</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Risk factors that predict a GH relapse after interrupting ATD therapy</span>&#58; The following factors are associated with a greater risk of relapse after withdrawing ATDs&#58; young age&#44; male sex&#44; tobacco use&#44; large goiter&#44; biochemistry indicating severe GH&#44; high levels of thyroid-stimulating immunoglobulins and&#44; more recently&#44; some genetic markers&#46; However&#44; none of these parameters has been shown to be useful for determining patients&#8217; individual prognoses&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8211;</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The response of patients with recurrent GH to other ATD cycles</span>&#58; Generally&#44; physicians believe that patients with recurrent GH do not usually respond effectively to new ATD cycles&#44; which leads them to choose RAI for these cases&#46; However&#44; previous and recent studies have demonstrated that a second ATD cycle in patients with recurrent GH leads to satisfactory long-term remission&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8211;</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The objective of RAI therapy and TT</span> is to reduce the functional mass of the thyroid tissue&#44; which results in athyreotic hypothyroidism &#40;AH&#41; whose management is complicated&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> Thyroid function should be monitored after ablation and the AH treated for life&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8211;</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The 3 therapeutic options are associated with problems and complications</span>&#58; The main problem with ATD therapy is relapses&#44; which occur in approximately 50&#37; of patients who discontinue the drug&#46; Given that the objective of RAI and TT is for the patient to develop hypothyroidism&#44; we cannot consider athyreotic hypothyroidism as a complication&#46; The main problem with RAI therapy is related to the progression of Graves&#8217; ophthalmopathy&#44; especially in patients who smoke and those with active ocular disease&#46; The safety and efficacy of TT is highly dependent on the surgeon&#39;s skill and experience&#46; RAI is related to increased morbidity and mortality due to cardiovascular disease&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> The clinical factors favoring TT are the large goiter with compression symptoms&#44; concurrent thyroid nodules suspected of malignancy and worsening ophthalmopathy&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> lists the complications associated with each treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">10&#8211;12</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8211;</span><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Long-term studies have shown the advantages of GH therapy with methimazole over</span><span class="elsevierStyleItalic">RAI</span><a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a>&#58; A systematic review and recent meta-analysis confirmed that long-term ADT therapy &#40;&#62;24 months&#41; is safe and effective&#44; although mainly in adults&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> Another study compared the efficacy and long-term safety of therapy with low-dose methimazole &#40;initial dose of 10&#8211;20<span class="elsevierStyleHsp" style=""></span>mg and maintenance dose of 2&#46;5&#8211;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#41; compared with RAI therapy in patients with GH relapse&#46; In this article&#44; the authors observed that in the low-dose methimazole group&#44; the rate of euthyroidism was higher than in the RAI group&#46; In contrast&#44; the rate of manifest and subclinical hypothyroidism was higher in the RAI group&#46; As has been previously observed&#44; RAI therapy was associated with a lack of improvement or worsening of Graves&#8217; ophthalmopathy&#46; None of the patients in the methimazole group developed relevant adverse effects&#46; RAI therapy was also associated with weight gain&#44; especially after 24 months of follow-up&#44; which is probably because the number of patients with subclinical and manifest hypothyroidism in this group was larger&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a></p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">In conclusion and considering the above&#44; extended low-dose metamizole is the best option for treating patients with recurrent GH in standard practice&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Garc&#237;a-Mayor RV&#46; Razones por las que considerar a las dosis bajas de metimazol como la mejor opci&#243;n para tratar a los pacientes con hipertiroidismo de Graves recurrente&#46; Rev Clin Esp&#46; 2019&#59;219&#58;168&#8211;170&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Advantages and disadvantages of the 3 therapeutic modalities for treating patients with recurrent Graves&#8217; hyperthyroidism&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; MMI&#58; methimazole&#59; RAI&#58; radioactive iodine&#59; TT&#58; total thyroidectomy&#46;</p>"
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