Editorial
Innovations in the therapeutic outlook of rheumatoid arthritis
Novedades en el Panorama Terapéutico de la Artritis Reumatoide
Santos Castañeda
, Isidoro González-Álvaro
Corresponding author
Servicio de Reumatología, Hospital de La Princesa, IIS-Princesa, Madrid, Spain
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Menéndez-Bueyes, María del Carmen Soler Fernández" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Luis R." "apellidos" => "Menéndez-Bueyes" ] 1 => array:2 [ "nombre" => "María del Carmen" "apellidos" => "Soler Fernández" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1699258X16000395" "doi" => "10.1016/j.reuma.2016.02.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X16000395?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574317300011?idApp=UINPBA00004M" "url" => "/21735743/0000001300000002/v2_201703100919/S2173574317300011/v2_201703100919/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Innovations in the therapeutic outlook of rheumatoid arthritis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "63" "paginaFinal" => "65" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Santos Castañeda, Isidoro González-Álvaro" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Santos" "apellidos" => "Castañeda" "email" => array:1 [ 0 => "scastas@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Isidoro" "apellidos" => "González-Álvaro" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Reumatología, Hospital de La Princesa, IIS-Princesa, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Novedades en el Panorama Terapéutico de la Artritis Reumatoide" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized as a cause of chronic inflammation of diarthrodial joints. As a consequence, the patients in whom it is diagnosed undergo a deterioration in the functional capacity and quality of life, as well as an increase in the mortality rate. Given that the prevalence of RA ranges between 0.5% and 1% of the general population,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> at the present time, between 30 and 60 million people around the world are RA patients, and their treatment constitutes an important economic and social cost.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The etiology of RA is unknown, although we know that smoking, high salt intake and obesity increase the risk of developing the disease,<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> and genetic variations in more than 100 genes have been reported to predispose individuals to acquire it.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Among the genetic factors, most of them are related to T-cell function, with human leukocyte antigen (HLA) class II being the region that accounts for more than 50% of the genetic risk of developing RA. However, it has also been associated with genes involving B-cell function, innate immunity and intracellular signaling related to the production of proinflammatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Due to these factors, its pathophysiology is highly complex, with different degrees of participation of the innate and adaptive immune systems depending on the groups of patients, and even on the phases of the disease. In any case, many of these pathophysiological pathways culminate in common final effector mechanisms, among which we should particularly point out tumor necrosis factor (TNF) and interleukin (IL) 6.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In addition, psychosocial factors have a role in making the presentation and clinical course, as well as the response to therapy, extremely heterogeneous. Nevertheless, it is indisputable that the management of RA has improved enormously in recent years as a consequence of the implementation of strategies for early detection and treatment that make it possible to take advantage of the “therapeutic window of opportunity”, as well as strategies for the close control and intensification of the treatment until the therapeutic objective, ideally remission, is accomplished. Although the cornerstone of these therapeutic strategies continues to be methotrexate, it is unquestionable that our enhanced ability to achieve the remission of RA is the availability of a therapeutic arsenal that has increased considerably over the last 15 years.</p><p id="par0020" class="elsevierStylePara elsevierViewall">At the present time, we have 3 types or families of slow-acting disease-modifying antirheumatic drugs (DMARD): (1) conventional synthetic (csDMARD) [methotrexate, leflunomide, salazopyrin, hydroxychloroquine and gold salts]; (2) biologic (bDMARD), which include 5 TNF antagonists, a T-cell costimulation blocker, a B-cell depleting agent and a IL-6 receptor antagonist; and (3) directed or <span class="elsevierStyleItalic">targeted</span> synthetic (tsDMARD), small molecules capable of crossing the cytoplasmic membrane and inhibiting, in quite a specific manner, different signaling pathways, especially the “Janus kinase/signal transducer and activator of transcription” (JAK/STAT) pathway. Nevertheless, despite the advances introduced, it is estimated that TNF inhibition is effective in only 20–50% of the patients after 6 months of treatment<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and that only 5–10% of RA patients achieve complete and sustained remission.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> With these questions still to be successfully addressed, the pharmaceutical industry is making a significant innovative effort to increase our therapeutic arsenal in the endeavor to increment these values. Among the new agents, those that represent a distinctive contribution to the mechanism of action are JAK kinase inhibitors and blockade of the granulocyte macrophage colony-stimulating factor (GM-CSF) cytokine, but we will also have access to novel agents acting as IL-6 antagonists and the number of biosimilars will continue to grow over the next few years.</p><p id="par0025" class="elsevierStylePara elsevierViewall">A number of cytokines relevant to the pathogenesis of RA (IL-6, IL-12, IL-15, IL-23, interferon and GM-CSF) signal through the JAK/STAT1 pathway.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Moreover, genetic variants of STAT1, STAT4 and TYK2 confer a higher risk for developing the disease.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Thus, it is logical that the European Medicines Agency recently approved, for use in patients with RA, 2 drugs that act on that pathway: tofacitinib (Xeljanz, Pfizer), a dual inhibitor of JAK1 and JAK3, and baricitinib (Incyte, Eli-Lilly), which acts by inhibiting preferentially JAK1 and JAK2. Both have shown excellent results both in csDMARD-naïve patients, and in patients with active moderate to severe RA and previous failure with csDMARD and/or anti-TNF, with a safety profile very much like that associated with IL-6 blockade, although with an incidence of herpes zoster somewhat higher in certain populations than that reported for other biologics. It is estimated that both will be available for use in Spain during the second half of 2017.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Another 2 inhibitors of the JAK/STAT pathway at an earlier phase of development are filgotinib (Galapagos/Gilead) and ABT-494 (AbbVie), specific JAK1 inhibitors. If they have a safe landing, they will consolidate the inhibition of the JAK/STAT pathway as one of the most competitive upcoming strategies in the treatment of RA in the near future.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Other new mechanisms of action being developed for the treatment of RA include the inhibition of colony-stimulating factors, especially GM-CSF, and the use of mesenchymal stem cells. Mavrilimumab (MedImmune/AstraZeneca) is the first monoclonal antibody against GM-CSF receptor α chain, and has aroused a great deal of interest. The excellent results in phase I and II trials in RA have sparked considerable expectations concerning the development of this molecule.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">With regard to the use of mesenchymal stem cells, recently published data show the findings in a controlled Ib/IIa clinical trial in patients with active RA refractory to ≥2 biologics. They were followed for 24 weeks after undergoing intravenous administration of mesenchymal stem cells from expanded allogeneic adipose-derived tissue.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This therapeutic approach, in which the mechanism of action is the induction of immunoregulatory substances and cells, was found to be safe and effective,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> although the duration of the response was limited. Therefore, its use in clinical practice is uncertain.</p><p id="par0045" class="elsevierStylePara elsevierViewall">On the other hand, given that IL-6 blockade has been shown to enable the control of the disease, on both the local and systemic level,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> at this time, plans for at least another 5 products that act through this mechanism of action are in the pipeline of several pharmaceutical companies, as occurred after the first anti-TNFα agent was introduced. Of these, we should point out sarilumab (Regeneron/Sanofi) and sirukumab (Janssen/GlaxoSmithKline), both of which are antibodies with a high affinity against IL-6 receptor, to be administered subcutaneously, that show efficacy data that are quite outstanding and safety profiles similar to that of tocilizumab.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,17,18</span></a> Others in less advanced phases of development include clazakizumab (Alder Biopharmaceuticals) and olokizumab (UCB/R-Pharm), which are humanized anti-IL-6 monoclonal antibodies, and ALX 0061 (Ablynx/AbbVie), also directed against IL-6 receptor.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In Spain, we currently have access to 3 infliximab biosimilars and 1 approved for etanercept. However, over the coming 2 years, biosimilars of adalimumab and rituximab will also be made available. This means that, in short, there will be 13 or 14 bDMARD and 2 tsDMARD. Undoubtedly, we will find that the number of RA patients that achieve remission will increase but, in turn, decision making will become more complex.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Until now, the prescription of a bDMARD follows an approach that combines the tactic of “trial and error”, with the evaluation of factors that are particular for each patient, such as the preference for a certain route of administration, frequency of use, family support, access to a hospital and associated comorbidity, as well as the previous experience of the prescribing physician. However, the arrival of biosimilars and the growing use of innovative therapies have put economic factors on the table that must be taken into account if we want the Spanish health system to be sustainable.</p><p id="par0060" class="elsevierStylePara elsevierViewall">During the next few years, we are going to observe a transformation in the approach to the treatment of RA, with new scenarios and opportunities. On the one hand, we have to see the attitude adopted by the pharmaceutical companies who are the proprietors of the existing innovating drugs whose patents have expired. On the other, the proprietors of new innovating drugs are going to touch down in a very competitive state of affairs. More important, the concept of “pay for performance” is beginning to be introduced. For this reason, we consider that the treatment of RA in the coming years will be a truly exciting field of research, given the challenges involving the need for: (i) biomarkers for the activity, prognoses and response to a given treatment, that make it possible to differentiate risk groups and the phenotypes of patients who may benefit from a certain class of drugs; and (ii) novel concepts of therapeutic response that are an improvement over those existing at the present time, which may be useful in clinical trials, but are found to be difficult to apply in real life. The objective will be to optimize the efforts made by physicians and the costs of the medication, improving the quality of life and safety of our patients.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">Dr. Castañeda is currently the principal investigator of a research project granted by the <span class="elsevierStyleItalic">Instituto de Salud Carlos III (ISCIII)</span>, Madrid, Spain, and Pfizer. Dr. Gonzalez-Álvaro is the principal investigator of several research projects granted by the <span class="elsevierStyleItalic">ISCIII</span> throughout the progress of this study. Dr. Gonzalez-Álvaro has also been the recipient of fees from Eli-Lilly, as well as grants, research funds and fees from UCB, BMS, Pfizer, Roche, AbbVie and MSD, not related to the objectives of this report. Dr. Gonzalez-Álvaro is also the holder of the intellectual property rights for patent PCT/ES2015/070182.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Castañeda S, González-Álvaro I. Novedades en el Panorama Terapéutico de la Artritis Reumatoide. Reumatol Clin. 2017;13:63–65.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L. Carmona" 1 => "M. Cross" 2 => "B. Williams" 3 => "M. Lassere" 4 => "L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 15 | 12 | 27 |
| 2024 October | 90 | 45 | 135 |
| 2024 September | 86 | 44 | 130 |
| 2024 August | 77 | 59 | 136 |
| 2024 July | 73 | 31 | 104 |
| 2024 June | 54 | 47 | 101 |
| 2024 May | 49 | 35 | 84 |
| 2024 April | 72 | 27 | 99 |
| 2024 March | 70 | 22 | 92 |
| 2024 February | 66 | 24 | 90 |
| 2024 January | 77 | 22 | 99 |
| 2023 December | 51 | 19 | 70 |
| 2023 November | 70 | 25 | 95 |
| 2023 October | 50 | 33 | 83 |
| 2023 September | 97 | 38 | 135 |
| 2023 August | 54 | 10 | 64 |
| 2023 July | 40 | 32 | 72 |
| 2023 June | 39 | 15 | 54 |
| 2023 May | 91 | 32 | 123 |
| 2023 April | 51 | 21 | 72 |
| 2023 March | 76 | 28 | 104 |
| 2023 February | 88 | 32 | 120 |
| 2023 January | 43 | 15 | 58 |
| 2022 December | 68 | 25 | 93 |
| 2022 November | 65 | 30 | 95 |
| 2022 October | 77 | 24 | 101 |
| 2022 September | 64 | 27 | 91 |
| 2022 August | 39 | 35 | 74 |
| 2022 July | 33 | 25 | 58 |
| 2022 June | 39 | 38 | 77 |
| 2022 May | 48 | 41 | 89 |
| 2022 April | 44 | 34 | 78 |
| 2022 March | 49 | 38 | 87 |
| 2022 February | 33 | 33 | 66 |
| 2022 January | 52 | 38 | 90 |
| 2021 December | 30 | 40 | 70 |
| 2021 November | 44 | 45 | 89 |
| 2021 October | 56 | 68 | 124 |
| 2021 September | 50 | 60 | 110 |
| 2021 August | 36 | 54 | 90 |
| 2021 July | 25 | 25 | 50 |
| 2021 June | 48 | 31 | 79 |
| 2021 May | 37 | 55 | 92 |
| 2021 April | 71 | 79 | 150 |
| 2021 March | 45 | 24 | 69 |
| 2021 February | 37 | 19 | 56 |
| 2021 January | 29 | 21 | 50 |
| 2020 December | 40 | 21 | 61 |
| 2020 November | 20 | 20 | 40 |
| 2020 October | 26 | 16 | 42 |
| 2020 September | 33 | 25 | 58 |
| 2020 August | 20 | 21 | 41 |
| 2020 July | 14 | 25 | 39 |
| 2020 June | 21 | 23 | 44 |
| 2020 May | 20 | 19 | 39 |
| 2020 April | 24 | 17 | 41 |
| 2020 March | 12 | 3 | 15 |
| 2019 February | 1 | 0 | 1 |
| 2018 September | 0 | 1 | 1 |
| 2018 May | 4 | 0 | 4 |
| 2018 April | 31 | 6 | 37 |
| 2018 March | 54 | 5 | 59 |
| 2018 February | 26 | 8 | 34 |
| 2018 January | 23 | 6 | 29 |
| 2017 December | 38 | 12 | 50 |
| 2017 November | 35 | 7 | 42 |
| 2017 October | 35 | 16 | 51 |
| 2017 September | 22 | 14 | 36 |
| 2017 August | 22 | 13 | 35 |
| 2017 July | 28 | 15 | 43 |
| 2017 June | 33 | 24 | 57 |
| 2017 May | 35 | 18 | 53 |
| 2017 April | 64 | 70 | 134 |
| 2017 March | 49 | 42 | 91 |
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