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recent years have seen changes in the therapeutic strategies in RA with early use of DMARDs and the introduction of biological therapies&#44; which led to better results in RA treatment&#44; in order to achieve remission or low disease activity level&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the 1990s various organizations&#44; such as the American College of Rheumatology &#40;ACR&#41; and the European League Against Rheumatism &#40;EULAR&#41; proposed a number of variables to be assessed at each patient visit and included the quantification of painful &#40;TJC&#41; and swollen joints &#40;SJC&#41;&#44; the assessment of pain and disease activity by both the patient and physician through a visual analog scale &#40;VAS&#41;&#44; functional capacity of patients and acute phase reactants &#40;ESR and CRP&#41;&#46; From these variables&#44; the proposed definitions of remission were&#58; the ACR through the fulfillment of criteria &#40;ACR criteria&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; and EULAR through an index &#40;DAS&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Another index that has been proposed is SDAI &#40;Simplified Disease Activity Index&#41;&#44; which has the advantage that it is performed through a calculated arithmetic sum of the SJC in 28 joints &#40;SJC28&#41;&#44; and TJC in 28 joints &#40;TJC28&#41;&#44; patient and physician VAS and CRP &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Although there are currently no remission criteria universally accepted&#44; these are the indices used&#46; Therefore&#44; both ACR and EULAR are working together to validate criteria that define what remission is&#44; and this collaboration has recently published provisional criteria whose application is intended for clinical<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> trials&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Remission can be defined as a state in which there is no inflammatory activity and no progression of structural damage&#46; This concept of remission is difficult to achieve in clinical practice&#44; because there the concept does not rule out the subclinical activity detectable by imaging<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> techniques&#46; Therefore&#44; many authors propose therapy to achieve a state of low disease activity as an alternative&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Withdrawal of Treatment in Remission of Early Rheumatoid Arthritis Patients</span><p id="par0025" class="elsevierStylePara elsevierViewall">It is increasingly clear that early treatment with DMARDs in RA results in lower long-term<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> radiological damage&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In RA there seems to be a period called &#8220;window of opportunity&#8221; in which the appropriate treatment may suppress or even reverse disease activity and lead the patient to an asymptomatic state&#44; slowing joint damage&#46; This window of opportunity presents itself at an early stage of the disease&#44; lasting approximately 12 weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> The need for early diagnosis has conditioned the recent publication by ACR and EULAR of diagnostic criteria for RA 9&#44; whose purpose is to achieve an earlier diagnosis of disease&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Among the studied that have reviewed the possible withdrawal of treatment in patients with early RA we find the following&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">A Finnish cohort of early RA &#40;n&#61;70 patients&#41; with a mean duration at the time of inclusion of 8 months was treated with DMARD monotherapy&#44; or in combination in cases of ineffective response&#46; They studied remission without medication and remission in a period of about 15 years&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Patients were divided into 3 groups according to the pattern of DMARD received&#46; DMARD were suspended only in patients who remained in remission with 1981 ACR criteria for at least 12 months or who for a long time had low disease activity without symptoms&#46; Twenty patients were able to discontinue medication&#44; of which 9 had to restart treatment after a mean 50 months&#44; most of them again reached low levels of activity&#46; One possible explanation might be that patients were in remission after stopping the medication and therefore only patients with true clinical remission should discontinue DMARDs&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The study enrolled 508 BeSt<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> patients with early RA of less than 2 years of progression &#40;mean disease duration of 23 weeks&#41; and were assigned to 4 treatment strategies&#58; sequential monotherapy with DMARDs &#40;group 1&#41;&#44; combined step-up therapy &#40;group 2&#41;&#44; combination therapy with high doses of prednisone &#40;group 3&#41; or with infliximab &#40;group 4&#41;&#46; Treatment adjustments were made every 3 months with the aim of reaching a state of low activity according to DAS &#40;DAS&#60;2&#46;4&#41;&#46; If the clinical response with monotherapy was adequate for 6 months&#44; medication was discontinued&#46; In the analysis of remission without treatment after 5 years of follow up&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> the authors found that 23&#37; of patients achieved remission without treatment&#44; without differences between groups&#44; but in 46&#37; of these patients DMARDs had to be restarted upon reactivation of the disease&#44; with retreatment being effective in 96&#37;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Withdrawal of Treatment in the Remission of Established Rheumatoid Arthritis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Patients with established RA &#40;more than 2 years of evolution&#41; have sequelae in the form of joint erosions&#46; In these patients&#44; the theory of &#8220;the window of opportunity&#8221; is no longer achievable to reverse the disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> so reaching remission without treatment is more complicated&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Various studies have addressed the suspension of treatment with DMARDs in patients with established RA in remission&#46; Among them we highlight the following&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In a Swiss cohort of 304 patients with established RA&#44; predictors of long-term remission were studied after stopping anti-TNF-&#945; therapy in patients who were in remission &#40;DAS28&#60;2&#46;6&#41; for at least 6 months with a stable dose of both the biologic and prednisone &#40;&#60;5<span class="elsevierStyleHsp" style=""></span>mg&#41; and without NSAID&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Twenty &#40;6&#46;9&#37;&#41; patients met criteria for stopping biological therapy with a mean time of 11&#46;3 years&#44; and a mean of 19&#46;4 months in remission with anti-TNF-&#945;&#46; At one year&#44; 16 &#40;71&#37;&#41; patients required re-treatment with anti-TNF-&#945; for recurrence after a mean 14&#46;7 weeks&#46; Baseline differences in patients who relapsed compared to those who remained in remission were the least time in treatment with anti-TNF-&#945; &#40;35 months vs 56 months&#41; and a shorter time in remission before stopping anti-TNF &#40;14&#46;5 months vs 35 months&#41;&#46; However&#44; the sample size was small&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In a Japanese multicenter study of induction of remission in RA treated with infliximab &#40;RRR study&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> those subjects who achieved a low level of activity &#40;DAS28&#60;3&#46;2&#41; for more than 24 months were invited to stay on infliximab&#46; One hundred and two patients&#44; of which 83 were in clinical remission&#44; with a mean disease duration of 5&#46;9 years&#44; agreed to suspend infliximab and participate in the study&#46; At one year&#44; 56 &#40;55&#37;&#41; patients remained on a low level of activity&#44; 44 of them in remission&#44; while the disease recurred in 46 patients&#46; In these&#44; retreatment with infliximab was effective in 32 of them reaching a low level of activity within 6 months&#46; Patients who achieved remission had lower duration of illness &#40;4&#46;8 vs 7&#46;8 years&#41; and less radiographic progression&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In a prospective study involving 47 patients with RA treated with methotrexate and biological therapy &#40;anti-TNF-&#945;&#41; in remission according to EULAR criteria &#40;DAS28&#60;2&#46;6&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> 27 patients &#40;mean duration of disease 19 months&#41; received combination therapy as first-line treatment for 12 months and 20 patients &#40;mean duration of illness of 120 months&#41; were treated with biological therapy &#40;anti-TNF-&#945;&#41; after inadequate response to DMARDs&#46; It was observed that a shorter duration of disease was a predictor of remission&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Recently&#44; there has been a meta-analysis of high-quality studies that included patients with RA of more than 2 years and in remission with DMARD treatment&#44; who suspended medication&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> It was observed that the suspension of medication must be done in a careful manner&#44; monitoring the degree of disease activity to restart treatment as early as possible&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0075" class="elsevierStylePara elsevierViewall">The therapeutic goal in RA is to attain remission or at least a low activity&#44; to introduce DMARD therapy as early as possible&#44; to induce remission or low disease activity and&#44; if feasible&#44; achieve remission without treatment&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We do not have enough information about patients who should stop treatment and when to stop it when remission of the disease is reached&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In early RA&#44; the &#8220;window of opportunity&#8221; can be used for treatment with DMARDs alone or in combination to induce remission and prevent radiological deterioration&#46; In patients with sustained clinical remission after a year of therapy&#44; one could try stopping the medication and closely monitoring patients looking for signs of activity in order to reintroduce therapy as soon as possible&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In established RA treatment&#44; discontinuation is more controversial&#46; One could try to suspend it in patients with RA in remission for at least a year&#44; with close monitoring to reintroduce it when activity is detected&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">There is no data to establish guidelines regarding the possibility of reducing treatment dose or prolonging the administration time interval&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Disclosures</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors have no disclosures to make&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xres125681"
          "titulo" => "Abstract"
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec112975"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres125682"
          "titulo" => "Resumen"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec112974"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Definition of Remission"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Withdrawal of Treatment in Remission of Early Rheumatoid Arthritis Patients"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Withdrawal of Treatment in the Remission of Established Rheumatoid Arthritis"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conclusions"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Disclosures"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2010-10-26"
    "fechaAceptado" => "2011-08-03"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec112975"
          "palabras" => array:4 [
            0 => "Anti-tumor necrosis factor-alpha"
            1 => "Disease modifying drugs"
            2 => "Remission"
            3 => "Rheumatoid arthritis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec112974"
          "palabras" => array:4 [
            0 => "Artritis reumatoide"
            1 => "F&#225;rmacos modificadores de la enfermedad"
            2 => "Remisi&#243;n"
            3 => "Tratamiento anti-factor de necrosis tumoral alfa"
          ]
        ]
      ]
    ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Rheumatoid arthritis is a chronic systemic inflammatory disease that causes significant morbidity and mortality&#46; The combined use of methotrexate and biological agents&#44; which directed against tumor necrosis factor &#40;TNF&#41; has achieved significant improvement in clinical&#44; radiographic and functional parameters not seen previously and has revolutionized the therapeutic goal of achieving remission in clinical&#44; structural and functional parameters&#46; The next goal should be to achieve remission without the use of biological drugs and later without medication&#46; Although there is evidence about the efficacy and safety of TNF inhibitors&#44; there is none on remission without the use of biological agents or disease modifying drugs&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La artritis reumatoide es una enfermedad inflamatoria cr&#243;nica sist&#233;mica que ocasiona una significativa morbilidad y mortalidad&#46; El uso combinado de metotrexato y agentes biol&#243;gicos dirigidos contra el factor de necrosis tumoral &#40;TNF&#41; ha logrado mejor&#237;as significativas en par&#225;metros cl&#237;nicos&#44; radiogr&#225;ficos y funcionales que no se hab&#237;an visto previamente y que han revolucionado el objetivo terap&#233;utico de conseguir la remisi&#243;n en par&#225;metros cl&#237;nicos&#44; estructurales y funcionales&#46; El pr&#243;ximo objetivo deber&#237;a ser alcanzar la remisi&#243;n sin el uso de f&#225;rmacos biol&#243;gicos y posteriormente sin medicaci&#243;n&#46; Aunque hay evidencia acerca de la eficacia y la seguridad de los inhibidores del TNF&#44; no la hay acerca de remisi&#243;n sin el empleo de agentes biol&#243;gicos ni f&#225;rmacos modificadores de la enfermedad&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; N&#243;voa Medina FJ&#44; Francisco Hern&#225;ndez F&#46; &#191;Se puede suspender la medicaci&#243;n en los pacientes con artritis reumatoide en remisi&#243;n&#63; Reumatol Clin&#46; 2012&#59;<span class="elsevierStyleBold">8&#40;1&#41;</span>&#58;39&#8211;41&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ACR&#58; American College of Rheumatology&#59; ESR&#58; Erythrocyte Sedimentation Rate&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span>At least 4 criteria must be present for at least 3 months&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Modified from Balsa&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46; Morning stiffness under 15 min&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46; Pain visual analog scale&#60;10<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46; No joint pain on examination&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5&#46; ESR&#60;30<span class="elsevierStyleHsp" style=""></span>mm&#47;h &#40;women&#41; or &#60;20<span class="elsevierStyleHsp" style=""></span>mm&#47;h &#40;men&#41;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Modified ACR Remission Criteria &#40;1995&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Modified from Balsa&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t  " align="left" valign="middle" style="border-bottom: 2px solid black">Degree of RA activity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="middle" style="border-bottom: 2px solid black">DAS&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">EULAR Remission Criteria &#40;DAS and DAS28&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Modified from Balsa&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  \t\t\t\t  " align="left" valign="middle" style="border-bottom: 2px solid black">Degree of RA activity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="middle" style="border-bottom: 2px solid black">SDAI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Remission&nbsp;\t\t\t\t\t\t\n
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">SDAI &#40;Simple Disease Activity Index&#41;&#46;</p>"
        ]
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    ]
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:15 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Smolen"
                            1 => "R&#46; Landew&#233;"
                            2 => "F&#46;C&#46; Breedveld"
                            3 => "M&#46; Dougados"
                            4 => "P&#46; Emery"
                            5 => "C&#46; Gaujoux-Viala"
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                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1136/ard.2009.126532"
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                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2010"
                        "volumen" => "69"
                        "paginaInicial" => "964"
                        "paginaFinal" => "975"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20444750"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0010"
              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Actualizaci&#243;n del Documento de Consenso de la Sociedad Espa&#241;ola de Reumatolog&#237;a sobre el uso de terapias biol&#243;gicas en la artritis reumatoide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Tornero Molina"
                            1 => "R&#46; Sanmart&#237;"
                            2 => "V&#46; Rodr&#237;guez"
                            3 => "E&#46; Mart&#237;n Mola"
                            4 => "J&#46;L&#46; Marenco"
                            5 => "I&#46; Gonz&#225;lez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.reuma.2009.10.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin"
                        "fecha" => "2010"
                        "volumen" => "6"
                        "paginaInicial" => "23"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21794674"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#191;C&#243;mo se eval&#250;a una respuesta inadecuada en un paciente con artritis reumatoide en la pr&#225;ctica cl&#237;nica&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46; Balsa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1699-258X(07)73597-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin"
                        "fecha" => "2007"
                        "volumen" => "3"
                        "paginaInicial" => "38"
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Continuing Medical Education
Can the Medication in Patients With Rheumatoidarthritis in Remission Be Stopped?
¿Se puede suspender la medicación en los pacientes con artritis reumatoide en remisión?
Francisco Javier Nóvoa Medinaa,
Corresponding author
fnovmed@hotmail.es

Corresponding author.
, Félix Francisco Hernándezb
a Servicio de Reumatología, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canarias, Las Palmas, Spain
b Servicio de Reumatología, Hospital de Gran Canaria Dr. Negrín. Las Palmas de Gran Canaria, Las Palmas, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is the most prevalent chronic inflammatory joint disease and affects 0&#46;5&#37;&#8211;1&#37; of the population of our country&#46; Without proper treatment it causes significant morbidity and mortality&#46; The introduction of biological therapies has significantly improved clinical outcomes and functional imaging of patients&#46; The therapeutic goal in clinical practice is to try to achieve remission or low disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Once achieved&#44; it is advisable &#40;if possible&#41; to reduce or remove biological treatment and reduction and removal of disease-modifying drugs &#40;DMARDs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The aim of this review is to analyze the possibility of suspending medication in patients with RA in prolonged remission and when the risk of recurrence exists with suspension&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Definition of Remission</span><p id="par0010" class="elsevierStylePara elsevierViewall">Although still far from curing the disease&#44; recent years have seen changes in the therapeutic strategies in RA with early use of DMARDs and the introduction of biological therapies&#44; which led to better results in RA treatment&#44; in order to achieve remission or low disease activity level&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the 1990s various organizations&#44; such as the American College of Rheumatology &#40;ACR&#41; and the European League Against Rheumatism &#40;EULAR&#41; proposed a number of variables to be assessed at each patient visit and included the quantification of painful &#40;TJC&#41; and swollen joints &#40;SJC&#41;&#44; the assessment of pain and disease activity by both the patient and physician through a visual analog scale &#40;VAS&#41;&#44; functional capacity of patients and acute phase reactants &#40;ESR and CRP&#41;&#46; From these variables&#44; the proposed definitions of remission were&#58; the ACR through the fulfillment of criteria &#40;ACR criteria&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; and EULAR through an index &#40;DAS&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Another index that has been proposed is SDAI &#40;Simplified Disease Activity Index&#41;&#44; which has the advantage that it is performed through a calculated arithmetic sum of the SJC in 28 joints &#40;SJC28&#41;&#44; and TJC in 28 joints &#40;TJC28&#41;&#44; patient and physician VAS and CRP &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Although there are currently no remission criteria universally accepted&#44; these are the indices used&#46; Therefore&#44; both ACR and EULAR are working together to validate criteria that define what remission is&#44; and this collaboration has recently published provisional criteria whose application is intended for clinical<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> trials&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Remission can be defined as a state in which there is no inflammatory activity and no progression of structural damage&#46; This concept of remission is difficult to achieve in clinical practice&#44; because there the concept does not rule out the subclinical activity detectable by imaging<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> techniques&#46; Therefore&#44; many authors propose therapy to achieve a state of low disease activity as an alternative&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Withdrawal of Treatment in Remission of Early Rheumatoid Arthritis Patients</span><p id="par0025" class="elsevierStylePara elsevierViewall">It is increasingly clear that early treatment with DMARDs in RA results in lower long-term<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> radiological damage&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In RA there seems to be a period called &#8220;window of opportunity&#8221; in which the appropriate treatment may suppress or even reverse disease activity and lead the patient to an asymptomatic state&#44; slowing joint damage&#46; This window of opportunity presents itself at an early stage of the disease&#44; lasting approximately 12 weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> The need for early diagnosis has conditioned the recent publication by ACR and EULAR of diagnostic criteria for RA 9&#44; whose purpose is to achieve an earlier diagnosis of disease&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Among the studied that have reviewed the possible withdrawal of treatment in patients with early RA we find the following&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">A Finnish cohort of early RA &#40;n&#61;70 patients&#41; with a mean duration at the time of inclusion of 8 months was treated with DMARD monotherapy&#44; or in combination in cases of ineffective response&#46; They studied remission without medication and remission in a period of about 15 years&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Patients were divided into 3 groups according to the pattern of DMARD received&#46; DMARD were suspended only in patients who remained in remission with 1981 ACR criteria for at least 12 months or who for a long time had low disease activity without symptoms&#46; Twenty patients were able to discontinue medication&#44; of which 9 had to restart treatment after a mean 50 months&#44; most of them again reached low levels of activity&#46; One possible explanation might be that patients were in remission after stopping the medication and therefore only patients with true clinical remission should discontinue DMARDs&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The study enrolled 508 BeSt<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> patients with early RA of less than 2 years of progression &#40;mean disease duration of 23 weeks&#41; and were assigned to 4 treatment strategies&#58; sequential monotherapy with DMARDs &#40;group 1&#41;&#44; combined step-up therapy &#40;group 2&#41;&#44; combination therapy with high doses of prednisone &#40;group 3&#41; or with infliximab &#40;group 4&#41;&#46; Treatment adjustments were made every 3 months with the aim of reaching a state of low activity according to DAS &#40;DAS&#60;2&#46;4&#41;&#46; If the clinical response with monotherapy was adequate for 6 months&#44; medication was discontinued&#46; In the analysis of remission without treatment after 5 years of follow up&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> the authors found that 23&#37; of patients achieved remission without treatment&#44; without differences between groups&#44; but in 46&#37; of these patients DMARDs had to be restarted upon reactivation of the disease&#44; with retreatment being effective in 96&#37;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Withdrawal of Treatment in the Remission of Established Rheumatoid Arthritis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Patients with established RA &#40;more than 2 years of evolution&#41; have sequelae in the form of joint erosions&#46; In these patients&#44; the theory of &#8220;the window of opportunity&#8221; is no longer achievable to reverse the disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> so reaching remission without treatment is more complicated&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Various studies have addressed the suspension of treatment with DMARDs in patients with established RA in remission&#46; Among them we highlight the following&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In a Swiss cohort of 304 patients with established RA&#44; predictors of long-term remission were studied after stopping anti-TNF-&#945; therapy in patients who were in remission &#40;DAS28&#60;2&#46;6&#41; for at least 6 months with a stable dose of both the biologic and prednisone &#40;&#60;5<span class="elsevierStyleHsp" style=""></span>mg&#41; and without NSAID&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Twenty &#40;6&#46;9&#37;&#41; patients met criteria for stopping biological therapy with a mean time of 11&#46;3 years&#44; and a mean of 19&#46;4 months in remission with anti-TNF-&#945;&#46; At one year&#44; 16 &#40;71&#37;&#41; patients required re-treatment with anti-TNF-&#945; for recurrence after a mean 14&#46;7 weeks&#46; Baseline differences in patients who relapsed compared to those who remained in remission were the least time in treatment with anti-TNF-&#945; &#40;35 months vs 56 months&#41; and a shorter time in remission before stopping anti-TNF &#40;14&#46;5 months vs 35 months&#41;&#46; However&#44; the sample size was small&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In a Japanese multicenter study of induction of remission in RA treated with infliximab &#40;RRR study&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> those subjects who achieved a low level of activity &#40;DAS28&#60;3&#46;2&#41; for more than 24 months were invited to stay on infliximab&#46; One hundred and two patients&#44; of which 83 were in clinical remission&#44; with a mean disease duration of 5&#46;9 years&#44; agreed to suspend infliximab and participate in the study&#46; At one year&#44; 56 &#40;55&#37;&#41; patients remained on a low level of activity&#44; 44 of them in remission&#44; while the disease recurred in 46 patients&#46; In these&#44; retreatment with infliximab was effective in 32 of them reaching a low level of activity within 6 months&#46; Patients who achieved remission had lower duration of illness &#40;4&#46;8 vs 7&#46;8 years&#41; and less radiographic progression&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In a prospective study involving 47 patients with RA treated with methotrexate and biological therapy &#40;anti-TNF-&#945;&#41; in remission according to EULAR criteria &#40;DAS28&#60;2&#46;6&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> 27 patients &#40;mean duration of disease 19 months&#41; received combination therapy as first-line treatment for 12 months and 20 patients &#40;mean duration of illness of 120 months&#41; were treated with biological therapy &#40;anti-TNF-&#945;&#41; after inadequate response to DMARDs&#46; It was observed that a shorter duration of disease was a predictor of remission&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Recently&#44; there has been a meta-analysis of high-quality studies that included patients with RA of more than 2 years and in remission with DMARD treatment&#44; who suspended medication&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> It was observed that the suspension of medication must be done in a careful manner&#44; monitoring the degree of disease activity to restart treatment as early as possible&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0075" class="elsevierStylePara elsevierViewall">The therapeutic goal in RA is to attain remission or at least a low activity&#44; to introduce DMARD therapy as early as possible&#44; to induce remission or low disease activity and&#44; if feasible&#44; achieve remission without treatment&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We do not have enough information about patients who should stop treatment and when to stop it when remission of the disease is reached&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In early RA&#44; the &#8220;window of opportunity&#8221; can be used for treatment with DMARDs alone or in combination to induce remission and prevent radiological deterioration&#46; In patients with sustained clinical remission after a year of therapy&#44; one could try stopping the medication and closely monitoring patients looking for signs of activity in order to reintroduce therapy as soon as possible&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In established RA treatment&#44; discontinuation is more controversial&#46; One could try to suspend it in patients with RA in remission for at least a year&#44; with close monitoring to reintroduce it when activity is detected&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">There is no data to establish guidelines regarding the possibility of reducing treatment dose or prolonging the administration time interval&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Disclosures</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors have no disclosures to make&#46;</p></span></span>"
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    "fechaRecibido" => "2010-10-26"
    "fechaAceptado" => "2011-08-03"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec112975"
          "palabras" => array:4 [
            0 => "Anti-tumor necrosis factor-alpha"
            1 => "Disease modifying drugs"
            2 => "Remission"
            3 => "Rheumatoid arthritis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec112974"
          "palabras" => array:4 [
            0 => "Artritis reumatoide"
            1 => "F&#225;rmacos modificadores de la enfermedad"
            2 => "Remisi&#243;n"
            3 => "Tratamiento anti-factor de necrosis tumoral alfa"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Rheumatoid arthritis is a chronic systemic inflammatory disease that causes significant morbidity and mortality&#46; The combined use of methotrexate and biological agents&#44; which directed against tumor necrosis factor &#40;TNF&#41; has achieved significant improvement in clinical&#44; radiographic and functional parameters not seen previously and has revolutionized the therapeutic goal of achieving remission in clinical&#44; structural and functional parameters&#46; The next goal should be to achieve remission without the use of biological drugs and later without medication&#46; Although there is evidence about the efficacy and safety of TNF inhibitors&#44; there is none on remission without the use of biological agents or disease modifying drugs&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La artritis reumatoide es una enfermedad inflamatoria cr&#243;nica sist&#233;mica que ocasiona una significativa morbilidad y mortalidad&#46; El uso combinado de metotrexato y agentes biol&#243;gicos dirigidos contra el factor de necrosis tumoral &#40;TNF&#41; ha logrado mejor&#237;as significativas en par&#225;metros cl&#237;nicos&#44; radiogr&#225;ficos y funcionales que no se hab&#237;an visto previamente y que han revolucionado el objetivo terap&#233;utico de conseguir la remisi&#243;n en par&#225;metros cl&#237;nicos&#44; estructurales y funcionales&#46; El pr&#243;ximo objetivo deber&#237;a ser alcanzar la remisi&#243;n sin el uso de f&#225;rmacos biol&#243;gicos y posteriormente sin medicaci&#243;n&#46; Aunque hay evidencia acerca de la eficacia y la seguridad de los inhibidores del TNF&#44; no la hay acerca de remisi&#243;n sin el empleo de agentes biol&#243;gicos ni f&#225;rmacos modificadores de la enfermedad&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; N&#243;voa Medina FJ&#44; Francisco Hern&#225;ndez F&#46; &#191;Se puede suspender la medicaci&#243;n en los pacientes con artritis reumatoide en remisi&#243;n&#63; Reumatol Clin&#46; 2012&#59;<span class="elsevierStyleBold">8&#40;1&#41;</span>&#58;39&#8211;41&#46;</p>"
      ]
    ]
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ACR&#58; American College of Rheumatology&#59; ESR&#58; Erythrocyte Sedimentation Rate&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span>At least 4 criteria must be present for at least 3 months&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Modified from Balsa&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t">1&#46; Morning stiffness under 15 min&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46; Pain visual analog scale&#60;10<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46; No joint pain on examination&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#46; No tendon or joint inflammation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5&#46; ESR&#60;30<span class="elsevierStyleHsp" style=""></span>mm&#47;h &#40;women&#41; or &#60;20<span class="elsevierStyleHsp" style=""></span>mm&#47;h &#40;men&#41;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Modified ACR Remission Criteria &#40;1995&#41;&#46;</p>"
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        "etiqueta" => "Table 2"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Modified from Balsa&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  \t\t\t\t  " align="char" valign="middle">&#60;1&#46;6&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">EULAR Remission Criteria &#40;DAS and DAS28&#41;&#46;</p>"
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        "etiqueta" => "Table 3"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Modified from Balsa&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p>"
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                  \t\t\t\t  " align="left" valign="middle" style="border-bottom: 2px solid black">SDAI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="middle">5&#8211;20&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">SDAI &#40;Simple Disease Activity Index&#41;&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:15 [
            0 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Smolen"
                            1 => "R&#46; Landew&#233;"
                            2 => "F&#46;C&#46; Breedveld"
                            3 => "M&#46; Dougados"
                            4 => "P&#46; Emery"
                            5 => "C&#46; Gaujoux-Viala"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2009.126532"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2010"
                        "volumen" => "69"
                        "paginaInicial" => "964"
                        "paginaFinal" => "975"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20444750"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Actualizaci&#243;n del Documento de Consenso de la Sociedad Espa&#241;ola de Reumatolog&#237;a sobre el uso de terapias biol&#243;gicas en la artritis reumatoide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Tornero Molina"
                            1 => "R&#46; Sanmart&#237;"
                            2 => "V&#46; Rodr&#237;guez"
                            3 => "E&#46; Mart&#237;n Mola"
                            4 => "J&#46;L&#46; Marenco"
                            5 => "I&#46; Gonz&#225;lez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.reuma.2009.10.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin"
                        "fecha" => "2010"
                        "volumen" => "6"
                        "paginaInicial" => "23"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21794674"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#191;C&#243;mo se eval&#250;a una respuesta inadecuada en un paciente con artritis reumatoide en la pr&#225;ctica cl&#237;nica&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46; Balsa"
                          ]
                        ]
                      ]
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                    0 => array:2 [
                      "doi" => "10.1016/S1699-258X(07)73597-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin"
                        "fecha" => "2007"
                        "volumen" => "3"
                        "paginaInicial" => "38"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21794394"
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              "etiqueta" => "4"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "American College of Rheumatology&#47;European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;T&#46; Felson"
                            1 => "J&#46;F&#46; Smolen"
                            2 => "G&#46; Wells"
                            3 => "B&#46; Zhang"
                            4 => "L&#46;H&#46;D&#46; Van Tuyl"
                            5 => "J&#46; Funovits"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.30129"
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                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2011"
                        "volumen" => "63"
                        "paginaInicial" => "573"
                        "paginaFinal" => "586"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21294106"
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              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Should imaging be a component of rheumatoid arthritis remission criteria&#63; A comparison between traditional and modified composite remission scores and imaging assessments"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Saleem"
                            1 => "A&#46;K&#46; Brown"
                            2 => "H&#46; Keen"
                            3 => "R&#46; Parmar"
                            4 => "S&#46; Nizam"
                            5 => "E&#46;M&#46;A&#46; Hensoret"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2010.134445"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2011"
                        "volumen" => "70"
                        "paginaInicial" => "792"
                        "paginaFinal" => "798"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21242236"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term impact of early treatment on radiographic progression in rheumatoid arthritis&#58; a metaanalysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Finckh"
                            1 => "M&#46;H&#46; Liang"
                            2 => "C&#46;M&#46; Van Herckenrode"
                            3 => "P&#46; De Pablo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.22353"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2006"
                        "volumen" => "55"
                        "paginaInicial" => "864"
                        "paginaFinal" => "872"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17139662"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                ]
              ]
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            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term impact of delay in assessment of patients with early arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;P&#46; Van der Linden"
                            1 => "S&#46; Le Cessie"
                            2 => "K&#46; Raza"
                            3 => "D&#46; vd Woude"
                            4 => "R&#46; Knevel"
                            5 => "T&#46;W&#46;J&#46; Huizinga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.27692"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2010"
                        "volumen" => "62"
                        "paginaInicial" => "3537"
                        "paginaFinal" => "3546"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20722031"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis classification criteria&#58; an American College of Rheumatology&#47;European League against Rheumatism Collaborative Initiative"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Aletaha"
                            1 => "T&#46; Neogi"
                            2 => "A&#46;J&#46; Silman"
                            3 => "J&#46; Funovits"
                            4 => "D&#46;T&#46; Felson"
                            5 => "C&#46;O&#46; Bingham III"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2010.138461"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
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ISSN: 21735743
Original language: English
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Idiomas
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