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such as abatacept&#44; rituximab and tocilizumab&#46; There are virtually no <span class="elsevierStyleItalic">head to head</span> studies between the various biological drugs&#44; but several meta-analyzes and systematic reviews show similar efficacy between them although some differences exist regarding their safety profile&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">With the introduction of these biological agents&#44; many patients who have been deemed DMARD refractory&#44; as in the case of RA or psoriatic arthritis&#44; or NSAIDs in the case of AS&#44; respond favorably and in a significant number there is a very good response&#44; even achieving a state of remission or low activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> These patients are initially treated with doses recommended by the data sheet according to the results of phase <span class="elsevierStyleSmallCaps">iii</span> clinical trials for product registration and approval by competent authorities&#44; but there is no consensus on what attitude to take in presence of sustained remission&#46; There are data in the literature that show that the abandonment of these therapies produces a clinical relapse of the disease in the majority of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> However&#44; some observational studies<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and recommendations by management guidelines for inflammatory arthritis such as RA<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> suggest the possibility of reducing the dose of biological agents in these patients to the lowest effective dose&#44; with the idea that some patients&#44; perhaps treated too intensively with standard doses&#44; could get the same benefit with a lower dose&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This dose reduction practice has been implemented empirically in recent years in the rheumatology practice&#44; 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as per diagnosis&#46; The objective of the study was to analyze how many patients were receiving a reduced dose of biological agent at the time of analysis&#44; study their characteristics and compare them to the group of patients who continued with a standard dose&#46; A &#8220;low-dose&#8221; was defined as a treatment regimen with a reduced amount of drug than that recommended in the data sheet for each product&#44; either by using lower doses or by increasing intervals between dose administration&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The reduced dose regimen was established empirically&#44; on the basis of a suitable control and maintenance of a level of the activity of the disease &#40;in most cases remission according to activity rates and for &#8805;12 months&#41; performed by the rheumatologist who assessed patients in clinical practice conditions&#44; although not using any strategy or default protocol&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The patients in whom the drug was suspended due to adverse events were removed from the study&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Each of the patients included came for a check-up visit&#44; and data collection at the time of the analysis was performed and reviewed&#44; retrospectively&#44; through clinical history data&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">We analyzed the following variables&#58; <span class="elsevierStyleItalic">demographics</span> &#40;gender and age&#41;&#44; <span class="elsevierStyleItalic">diagnosis</span> years of evolution of the disease&#44; <span class="elsevierStyleItalic">previous treatment</span> &#40;synthetic and biological DMARDs&#41;&#44; <span class="elsevierStyleItalic">current biological treatment</span> &#40;type&#44; dose and duration of biological therapy&#41; and <span class="elsevierStyleItalic">current and concomitant treatment</span> &#40;synthetic DMARDs and&#47;or corticosteroids&#41;&#46; In patients diagnosed with RA we also determined serum ESR and CRP at the time of inclusion&#59; and calculated the <span class="elsevierStyleItalic">compound clinical activity index</span> DAS28 <span class="elsevierStyleItalic">at the time of analysis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In those patients receiving reduced biological doses at the time of analysis we studied&#58; the <span class="elsevierStyleItalic">reason</span> for dose reduction&#44; reduced <span class="elsevierStyleItalic">time-dose</span> and <span class="elsevierStyleItalic">clinical decision</span> at the time of analysis &#40;maintenance or biological agent at a reduced dose&#41;&#46; In patients receiving standard biological doses at the time of inclusion we analyzed whether such a reduction had been previously tried&#46; We also examined whether there were differences in the variables included in both groups &#40;low dose vs normal dose&#41;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical Analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">A descriptive study was conducted using measures of central tendency &#40;mean&#41; and dispersion &#40;standard deviation&#41; for continuous variables&#44; and percentages for qualitative variables&#46; We performed a comparative analysis of the 2 groups of patients &#40;reduced dose vs normal dose&#41; using the Chi-square test for qualitative variables&#44; and Student&#39;s <span class="elsevierStyleItalic">t</span>-for quantitative variables&#46; Significance was set at <span class="elsevierStyleItalic">P</span>&#60;&#46;05&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">From June 2011 to November 2011 a total of 169 patients were initially included of whom some were excluded for not receiving the biological agent at the time of assessment &#40;n<span class="elsevierStyleMonospace">&#61;</span>2&#41; or because the treatment duration was less than 6 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>14&#41;&#46; Of the 153 patients included in the final analysis&#44; 63&#46;3&#37; were women and the average age was 51 years&#46; The main diagnosis was RA in 53&#46;5&#37; of patients&#46; Other diagnoses were&#58; EA &#40;18&#46;5&#37;&#41;&#44; PsA &#40;13&#46;5&#37;&#41; and miscellaneous &#40;14&#46;5&#37;&#41;&#44; including 8 juvenile idiopathic arthritis&#44; 3 undifferentiated spondyloarthropathy&#44; 3 seronegative polyarthritis&#44; 3 uveitis&#44; 2 palindromic rheumatism&#44; one mixed connectivetissue disease and one case of SAPHO syndrome and Still&#39;s disease&#46; Baseline characteristics of all patients examined&#44; as well as patients per group &#40;low and standard dose&#41; are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; At the time of analysis&#44; 70 patients &#40;45&#46;7&#37;&#41; received a reduced dose of biological either due to a decrease in dosage or an increase of the administration interval&#46; In none of the patients with reduced doses was a dose decreased due to adverse effects&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">25&#46;5&#37; of patients had previously received other biologic drugs&#44; with this circumstance being less frequent in the group of patients with reduced doses than in patients with standard doses&#44; although these differences did not reach statistical significance&#46; No differences were seen in the duration of the current biological therapy in both groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In most patients&#44; current biological therapy includes the anti-TNF drugs&#44; with no significant difference between the 2 groups&#46; In the group of patients with reduced dose&#44; the average time for such a reduction was 17&#46;4&#177;17&#46;5 months&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">When reduced dose patients were analyzed with respect to the biologic drug used&#44; 57&#46;6&#37; of those receiving adalimumab were receiving a reduced dose&#44; 54&#46;9&#37; of those taking etanercept&#44; 40&#37; of those receiving tocilizumab and 14&#46;3&#37; of patients treated with infliximab&#46; No dose reduction was seen in patients treated with other biologics&#46; The most employed reduced dose was 50<span class="elsevierStyleHsp" style=""></span>mg&#47;10 days etanercept &#40;48&#46;7&#37; of patients with reduced dose of etanercept&#41;&#44; 40<span class="elsevierStyleHsp" style=""></span>mg&#47;21 days for adalimumab &#40;78&#46;9&#37;&#41;&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;9 weeks for infliximab &#40;50&#37;&#41; and 6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4 weeks for tocilizumab &#40;87&#46;5&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; When we analyzed the group of patients with a reduced dose with regard to the underlying disease&#44; 50&#37; of those in the miscellaneous group had a reduced dose&#44; as well as 50&#37; of PsA&#44; 48&#46;2&#37; of patients with AS&#44; and 42&#46;6&#37; of RA&#46; 24 of the 83 patients receiving a standard dose &#40;28&#46;9&#37;&#41; had previously tried to reduce biologic drug dose without success&#44; having to return to the normal dose&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In patients diagnosed with RA no significant differences were seen in demographic characteristics&#44; duration of illness and duration of current biological therapy between the standard-dose group and low-dose group&#44; although in patients with a reduced dose the frequency of use NSAIDs and corticosteroids was significantly lower &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In RA patients there were no significant differences between patients with reduced doses and standard dose patients&#44; taking into account with patients with reduced dose having less concomitant use of DMARD and glucocorticoid compared to patients with standard doses &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; No differences were observed between groups regarding the duration of the disease&#46; When retrospectively analyzed&#44; values of disease activity at the time of the decision to reduce the dose were on average DAS28 2&#46;31&#177;0&#46;52&#44; whereas at the moment the data were collected it was 2&#46;32&#177;0&#46;72 &#40;no significant difference&#41;&#46; As expected when comparing the mean DAS28 between the low dose group and standard dose group&#44; significantly lower values were observed in the low dose group compared to the standard system&#46; Significant differences were also seen in the mean CRP and ESR values in both groups&#46; Similarly&#44; the percentage of patients in remission or low disease activity was significantly higher in the low dose group &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; In RA patients&#44; the reason for dose reduction was disease remission &#40;DAS28&#8804;2&#46;6&#41; in 32 patients &#40;91&#46;4&#37;&#41; and low activity &#40;DAS28 3&#46;2 and &#62;2&#46;6&#41; in 3 &#40;8&#46;6&#37;&#41;&#46; The mean time of dose reduction in these patients was 13&#46;6&#177;11&#46;9 months&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">In patients with reduced dose&#44; the therapeutic decision at the time of data collection was&#58; keep the dose reduced in 94&#46;3&#37; &#40;66 patients&#41;&#44; further reduce the dose of the drug in 3 patients &#40;4&#46;3&#37;&#41; and increase it in one patient &#40;1&#46;4&#37;&#41; according to the disease activity&#44; as assessed by clinical judgment and normal disease indexes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">In this study we analyze the frequency and characteristics of patients treated in our hospital who were being treated with low doses of biologics in clinical practice conditions&#44; having achieved adequate control of the disease&#44; comparing them with those receiving standard doses&#46; This transversal analysis confirms that a significant number of patients &#40;45&#46;7&#37;&#41; treated with biological drugs receive a reduced dose&#44; and the said dose is applied to various inflammatory arthritis&#44; and many such patients were receiving low doses for a relatively prolonged period of time &#40;mean 17 months&#41;&#44; maintaining remission or low disease activity&#46; There are differences between patients with reduced doses compared to standard-doses regarding concomitant use of DMARDs&#44; corticosteroids and NSAIDs&#46; In the case of RA and&#44; as expected&#44; lower dose patients showed a clear reduced disease activity and high rates of remission compared with patients with standard doses&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A clinical situations facing today&#39;s clinical rheumatologist is how to decide to follow the therapeutic approach in patients with adequate control of the disease under biological therapy&#44; remission or low activity extended in time&#46; Although most patients with RA and other inflammatory arthropathies are not in remission under these biological agents&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> there is no doubt that this goal&#44; or that of attaining a low disease activity&#44; can be achieved in a significant number of cases&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Biological drug withdrawal in these cases is followed&#44; in most cases&#44; of a clinical relapse within a few months&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> However&#44; observational studies of therapeutic strategy&#44; such as the BEST study demonstrate that the biological removal is possible in a high percentage of cases&#59; in this study&#44; more than half of the patients who had taken an initial strategy of infliximab plus methotrexate left infliximab after reaching low disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> However&#44; this possibility is more evident in those patients in whom the biological is administered as a first option&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> something unusual in the current strategy for RA treatment&#44; where the biological agent is virtually always used when one or more synthetic DMARD<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> have failed&#46; However&#44; such removal appears to be possible also in the case of RA in patients after failure to DMARDs&#44; as suggested by a Japanese study&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> although cases which would benefit from the removal would be those with little time since onset of RA&#44; but not those with a evolved disease as a new study by the Emery Group suggests&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Under this prism of high probability of clinical recurrence in patients who leave biological therapy once remission is achieved&#44; it sounds logical to take an intermediate position as would be the progressive dose reduction &#40;or increase in the dosing interval&#41; along with monitoring the disease activity&#46; In the current EULAR recommendations for the management of patients with RA<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> it is established that if a patient with RA achieves permanent remission &#40;12 months&#63;&#41; and is able to suspend steroids&#44; a strategy for biological dose reduction may be considered&#44; especially if the patient is being treated with DMARDs&#46; This recommendation&#44; based on expert opinion&#44; is being used empirically in clinical practice in different inflammatory arthropathies&#44; with some groups contributing their own experiences&#44; both in SA AR&#44;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;17&#8211;20</span></a> or<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> PsA with good results&#44; although some results have been obtained only through conference papers&#46; The SER&#44; in their consensus document on the use of biological therapies in RA<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> states that&#44; in patients who have achieved remission&#44; acceptable options are to maintain the biological agent&#44; try to lower the dose&#44; increase the dosing interval or even suspend the biological agent&#44; as long as the patient remains in clinical remission for a time yet to be defined&#46; However&#44; in the consensus document for PsA it is stated that there is no current evidence to recommend biological reduction in this disease&#44; although it can be considered individually&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In the case of AS&#44; the SER consensus postulates that in selected patients with minimal clinical activity such a reduction may be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The first description in the literature on the results of the reduction of the dose of biological agents in patients with arthritis dates back to 2002 when a Dutch group found that in a small group of patients with RA treated with adalimumab&#44; 76&#37; were able to reduce TNF antagonist doses&#44; with monitoring of the disease activity with DAS28&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The same group of authors stated in a recent editorial<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> that dose reduction is possible in patients with RA&#44; arguing that there is <span class="elsevierStyleItalic">overtreatment</span> in a significant number of patients in whom the dose may be reduced while achieving the same clinical benefit&#44; and in this sense monitoring of drug levels could be useful to the clinician&#46; These same authors also proved that in most patients with RA who had increased the dose of infliximab 3&#8211;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; a position with questionable evidence&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> the dose can be reduced to 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg without increasing disease activity as measured by DAS28&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">To the best of our knowledge only one randomized trial existed earlier which analyzes whether reduced biological dose can maintain control of the disease in patients who have achieved a low disease activity with standard biological dose&#46; The PRESERVE studied&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> RA patients with moderate activity as measured by DAS28&#44; who had achieved adequate control of RA &#40;DAS28<span class="elsevierStyleMonospace">&#60;</span>3&#46;2&#41; with standard doses of etanercept &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41; plus methotrexate and who were randomized to three treatment arms&#58; follow standard dose&#44; mid-dose &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41; and complete withdrawal and where then followed for one year&#46; Most patients still on etanercept maintained the low activity and no differences between those receiving a standard dose or reduced dose &#40;82&#46;6&#37; and 79&#46;1&#37; respectively&#41; was seen&#44; while in the patients who were withdrawn from the biological this percentage is significantly reduced &#40;42&#46;6&#37;&#41;&#46; Interestingly&#44; there are also differences in radiographic progression between the two groups of patients treated with etanercept&#46; In fact&#44; a French retrospective study showed a similar clinical response in patients with RA and AS when comparing &#8211; etanercept 25<span class="elsevierStyleHsp" style=""></span>mg 2 times&#47;week &#8211; with etanercept 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> However&#44; although the PRESERVE study is interesting and scientifically supports the strategy of etanercept dose reduction is possible in a significant number of patients with RA&#44; it must be remembered that the patients included had moderately active RA&#44; so these results cannot be extrapolated to patients who begin with high activity &#40;DAS28&#62;5&#46;1&#41;&#44; a circumstance which occurs for example in 62&#37; of RA patients in our service &#40;unpublished data&#41; or those starting other biological drugs&#46; It is unknown if there are similar studies in patients with PsA&#46; As for the SA or axial spondyloarthritis&#44; there is an ongoing national randomized study of dose reduction with TNF antagonists in 190 patients sponsored by the Spanish Foundation of Rheumatology and Spanish Society of Clinical Pharmacology &#40;REDES study&#41; that will undoubtedly provide data on this issue&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The reduced biological dose was used in this series in a similar percentage in the 4 groups of patients classified according to diagnosis&#44; though somewhat lower in patients with RA&#46; A recent study in patients with early disease who had gone into remission with adalimumab at a standard dose &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;2 weeks&#41;&#44; points out that the ability to maintain this remission with increased dosing intervals &#40;adalimumab 40<span class="elsevierStyleHsp" style=""></span>mg&#47;4 weeks&#41; would be much more frequent in PsA than in RA<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#59; however&#44; it should be noted that our strategy of dose reduction in these diseases never contemplated the move to a monthly dose without first undergoing adalimumab treatment at a dose of 40<span class="elsevierStyleHsp" style=""></span>mg&#47;3 weeks&#46; Moreover&#44; it is interesting that in our study there were no differences in the time of disease progression or duration of current biological therapy between the groups with and without dose reduction&#44; although it was less frequent to see the use of prior biological agents in patients with dose reduction&#46; It is of interest&#44; in the case of RA&#44; to see the reduced use of concomitant DMARDs in patients with reduced doses&#44; a fact which certifies that patients with biological agents alone could also benefit from the reduction of dose&#46; As expected&#44; due to the decision to reduce the dose when the patient was in permanent clinical remission and occasionally in low activity&#44; reduced dose RA patients showed high remission rates&#44; lower disease activity and lower frequency of concomitant treatment with corticosteroids than patients with standard doses&#44; all data that would support the fact that such a reduction is possible in these patients to maintain adequate control of the disease&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The present study&#44; however&#44; has a number of limitations that should be mentioned&#46; First&#44; it is an observational study of clinical practice&#44; with a relatively small number of patients without any pre-established protocol&#44; so the decision and the moment to proceed with dose reduction are at the discretion of the investigator only&#46; Secondly&#44; the dose reducing regimen was also empirical and was done progressively&#44; while always taking into account the activity of the disease and&#44; in the case of clinical relapse&#44; returning to the standard dose and&#44; in fact&#44; a significant percentage of patients in this series had previously tried to reduce the dose&#44; but were back with the standard dose after the target had not been achieved&#59; we did not specifically examine predictors of recurrence in these patients&#46; Third&#44; it is a cross-sectional study&#44; so we do not know whether this reduction may or may not be sustained over time or result in a loss of clinical benefit in the medium to long term&#44; not only in terms of disease activity&#44; but also in functional capacity&#44; structural damage or even on the immunogenicity of these drugs&#46; However&#44; the fact that the average dose reduction in these patients was relatively prolonged &#40;17 months&#41; at the time of the evaluation and the fact that these patients remained in remission or low activity strongly suggests that such a reduction is possible in a number of patients followed in our clinical practice&#46; Fourth&#44; our experience with reduced biological dose is based primarily on etanercept&#44; adalimumab and tocilizumab and to a lesser extent&#44; infliximab&#46; We have no experience in terms of dose reduction&#44; for obvious reasons&#44; with other biological drugs such as golimumab or certolizumab&#44; nor with non-anti-TNF agents such as abatacept and rituximab&#46; In the latter case&#44; randomized trials with DMARD failing patients suggest a similar clinical efficacy between &#8211; a dose of 1<span class="elsevierStyleHsp" style=""></span>g &#40;2&#215;500<span class="elsevierStyleHsp" style=""></span>mg&#41; and 2<span class="elsevierStyleHsp" style=""></span>g &#40;2&#215;1000<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> In the recent EULAR 2012 meeting held in Berlin&#44; 2 studies examined rituximab dose reduction to 500<span class="elsevierStyleHsp" style=""></span>mg from the second cycle with conflicting results&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Finally&#44; we evaluated the incidence of adverse effects or costs associated with dose reduction&#46; Although it is unknown if dose reduction would achieve a significant reduction of adverse effects&#44; it is clear that it reduces costs&#44; at least in terms of direct costs and could be cost-effective&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> In fact&#44; we believe this strategy has allowed to greatly control expenditure on biologicals in our hospital&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In summary&#44; it is possible to reduce the dose of biological agents in patients with inflammatory arthritis in remission or low activity initially treated with standard doses&#44; achieving adequate control of the disease in many cases of routine clinical practice&#46; However&#44; there are virtually no studies designed to determine the effectiveness of dose reduction strategies&#44; so this practice is still empirical for clinical rheumatologist&#46; The publication of some studies&#44; and the strategies on dose reduction protocols are needed to support this clinical practice that is commonly used in many rheumatology services and&#44; possibly&#44; will be increased in the context of the current economic crisis and strict control of health spending&#46; It seems natural that&#44; in all the optimization strategies of the different drug treatment for inflammatory arthritis&#44; reducing the dose of biological agents should play a predominant role&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protection of people and animals</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that experiments have not been performed on humans or animals&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Data confidentiality</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Right to privacy and informed consent</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of patients and&#47;or subjects referred to in the article&#46; This document is in the possession of the corresponding author&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of Interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To analyze the frequency and characteristics of dose reduction of biological agents in a cohort of patients with chronic arthritis&#44; in clinical practice conditions in a tertiary level hospital&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Descriptive&#44; cross-sectional study&#44; which included all patients&#44; followed consecutively during 6 months &#40;June 2011&#8211;November 2011&#41;&#44; by one investigator&#44; with patients who at least have received one dose of biological agents in 2011&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We included 153 patients&#58; rheumatoid arthritis &#40;RA&#41; &#40;n<span class="elsevierStyleMonospace">&#61;</span>82&#41;&#44; ankylosing spondylitis &#40;n<span class="elsevierStyleMonospace">&#61;</span>29&#41;&#44; psoriatic arthritis &#40;n<span class="elsevierStyleMonospace">&#61;</span>20&#41;&#44; and miscellaneous group &#40;n<span class="elsevierStyleMonospace">&#61;</span>22&#41;&#46; Mean disease duration was 14&#46;9&#177;7&#46;7 years&#46; At the time of analysis&#44; 70 patients &#40;45&#46;7&#37;&#41; were receiving low doses of biological therapy &#40;50&#37; in miscellaneous group group&#44; 50&#37; in psoriatic arthritis&#44; 48&#46;2&#37; in ankylosing spondylitis&#44; and 42&#46;6&#37; in RA&#41;&#46; Mean time of dosage reduction was 17&#46;4&#177;17&#46;5 months&#46; The most common biological agents used in low dose were&#58; etanercept&#44; adalimumab and tocilizumab in 57&#46;6&#37;&#44; 54&#46;9&#37;&#44; and 40&#37; respectively&#44; in patients with a reduced dose of biological therapy&#46; The patients at low dose of biological therapy compared with standard dose had similar mean disease duration&#44; but received significantly less DMARDs&#44; glucocorticoids and NSAIDs&#44; and similar biological agent duration&#46; RA patients with reduced biological treatment&#44; at the time of analysis&#44; had higher remission rates versus patients receiving a standard dose &#40;82&#46;9&#37; vs 34&#37;&#44; <span class="elsevierStyleItalic">P</span>&#60;&#46;0001&#41;&#46; The medical decision at the time of analysis was to maintain low-dosage biological treatment in almost all patients&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In our clinical practice&#44; 45&#46;7&#37; of our chronic arthritis patients receive low dose of biological therapy&#44; after achieving remission or low activity at standard doses&#44; maintaining a good control of the disease&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Analizar la frecuencia y caracter&#237;sticas de la reducci&#243;n de dosis de f&#225;rmacos biol&#243;gicos en una cohorte de pacientes con artritis cr&#243;nica&#44; en condiciones de pr&#225;ctica cl&#237;nica de un hospital de tercer nivel&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo y transversal&#44; que incluy&#243; a todos los pacientes visitados consecutivamente durante 6 meses &#40;junio de 2011-noviembre de 2011&#41; por un solo investigador&#44; con pacientes que hab&#237;an recibido al menos una dosis de f&#225;rmaco biol&#243;gico durante el a&#241;o 2011&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 153 pacientes&#58; artritis reumatoide &#40;AR&#41; &#40;n<span class="elsevierStyleMonospace">&#61;</span>82&#41;&#44; espondilitis anquilosante &#40;n<span class="elsevierStyleMonospace">&#61;</span>29&#41;&#44; artritis psori&#225;sica &#40;n<span class="elsevierStyleMonospace">&#61;</span>20&#41; y grupo miscel&#225;nea &#40;n<span class="elsevierStyleMonospace">&#61;</span>22&#41; con una evoluci&#243;n media de 14&#44;9 &#177; 7&#44;7 a&#241;os&#46; En el momento del an&#225;lisis&#44; 70 pacientes &#40;45&#44;7&#37;&#41; estaba con dosis reducida &#40;un 50&#37; en el grupo miscel&#225;nea&#59; un 50&#37; en artritis psori&#225;sica&#59; un 48&#44;2&#37; en espondilitis anquilosante&#44; y un 42&#44;6&#37; en AR&#41;&#46; El tiempo medio de reducci&#243;n de dosis fue de 17&#44;4 &#177; 17&#44;5 meses&#46; Los f&#225;rmacos biol&#243;gicos m&#225;s utilizados a dosis reducidas fueron&#58; etanercept&#44; adalimumab y tocilizumab&#59; el 57&#44;6&#44; el 54&#44;9 y el 40 respectivamente de los pacientes tratados con estos agentes lo hac&#237;an a dosis reducidas&#46; Los pacientes con dosis reducidas en comparaci&#243;n con aquellos con dosis normales ten&#237;an un mismo tiempo de evoluci&#243;n de la enfermedad&#44; pero recib&#237;an menos FAME&#44; glucocorticoides y AINE&#44; con un tiempo similar de uso del agente biol&#243;gico&#46; Los pacientes con AR y dosis reducidas ten&#237;an&#44; en el momento del an&#225;lisis&#44; mayores &#237;ndices de remisi&#243;n que los pacientes con dosis normales &#40;82&#44;9 vs&#46; 34&#37;&#44; p &#60; 0&#44;0001&#41;&#46; La decisi&#243;n terap&#233;utica en el momento del an&#225;lisis fue mantener la dosis reducida en la pr&#225;ctica totalidad de los pacientes&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En nuestra pr&#225;ctica cl&#237;nica&#44; el 45&#44;7&#37; de los pacientes con artritis cr&#243;nica reciben terapia biol&#243;gica a dosis reducidas&#44; tras haber alcanzado la remisi&#243;n o baja actividad a dosis est&#225;ndares&#44; manteniendo la mayor&#237;a de ellos un buen control de la enfermedad&#46;</p>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9674;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Jos&#233; Inciarte-Mundo and M&#46; Victoria Hern&#225;ndez have participated equally in the design and elaboration of the study and manuscript&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Inciarte-Mundo J&#44; Hern&#225;ndez MV&#44; Rosario V&#44; Ruiz-Esquide V&#44; Cabrera-Villalba S&#44; Ram&#237;rez J&#44; et al&#46; Reducci&#243;n de dosis de terapias biol&#243;gicas en enfermedades reum&#225;ticas&#58; an&#225;lisis descriptivo de 153 pacientes en condiciones de pr&#225;ctica cl&#237;nica&#46; Reumatol Clin&#46; 2014&#59;10&#58;10&#8211;16&#46;</p>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">PsA&#58; psoriatic arthritis&#44; RA&#58; rheumatoid arthritis&#44; SA&#58; ankylosing spondylitis&#44; m&#58; months&#44; n&#58; number&#44; NS&#58; not significant&#44; TNF&#58; tumor necrosis factor&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">In bold&#44; statistically significant data&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Total patients&#44; n<span class="elsevierStyleMonospace">&#61;</span>153&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with standard biological dose&#44; n<span class="elsevierStyleMonospace">&#61;</span>83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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" style="border-bottom: 2px solid black">Patients with reduced biological dose&#44; n<span class="elsevierStyleMonospace">&#61;</span>70&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">52&#46;1&#177;13&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#46;8&#177;15&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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"><span class="elsevierStyleItalic">Gender &#40;female&#41; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><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">63&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">55&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time since onset of disease &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&#46;7&#177;14&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">8&#46;0&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">7&#46;3&#177;14&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">NS&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="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RA&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  " align="left" valign="\n
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                  \t\t\t\t">35 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SA&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 &#40;18&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">15 &#40;18&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">14 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&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"><span class="elsevierStyleHsp" style=""></span>PsA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Miscellaneous<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;14&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;13&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;15&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><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">&#8805;2 <span class="elsevierStyleItalic">prior biological agents&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;13&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;7&#41;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 &#40;25&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;30&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-TNF&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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  " align="left" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">55&#46;3&#177;38&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">54&#46;9&#177;29&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-TNF&#44; n &#40;&#37;&#41;&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">125 &#40;81&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">63 &#40;75&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">62 &#40;88&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8 &#40;11&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">15 &#40;21&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>40<span class="elsevierStyleHsp" style=""></span>mg&#47;30 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">4 &#40;5&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tocilizumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">8 &#40;11&#46;4&#41;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4 weeks&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1 &#40;1&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with biological standard dose&#44; n&#61;36&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">45&#46;3&#177;12&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#46;1&#177;12&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;1&#177;14&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">NS&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">45 &#40;63&#46;3&#41;&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">21 &#40;58&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">24 &#40;68&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time since onset of disease &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8&#46;1&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;9&#177;14&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant DMARD&#44; n &#40;&#37;&#41;</span>&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="\n
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                  \t\t\t\t">18 &#40;25&#46;3&#41;&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">10 &#40;27&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;22&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;16&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;13&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Leflunomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sulfasalazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant corticosteroids&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;15&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;22&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;&#46;0001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant NSAIDs&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;50&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;69&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;31&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Current biological therapy duration&#44; &#40;m&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;2&#177;30&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#177;36&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#177;29&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Current biological drug&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-TNF&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">67 &#40;94&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33 &#40;91&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;97&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Non anti TNF&#44; n &#40;&#37;&#41;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Anti-CCP&#58; cyclic citrullinated peptide antibody&#59; DMARD&#58; disease-modifying anti-rheumatic drug&#44; m&#58; months&#44; n&#58; number&#44; NS&#58; not significant&#44; CRP&#58; C-reactive protein&#44; TNF&#58; tumor necrosis factor&#44; ESR&#44; erythrocyte sedimentation rate&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">In bold&#44; statistically significant data&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Total patients&#44; n&#61;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with biological standard dose&#44; n&#61;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with reduced biological dose&#44; n<span class="elsevierStyleMonospace">&#61;</span>35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#46;1&#177;12&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#46;5&#177;11&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;5&#177;12&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Gender &#40;female&#41;&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70 &#40;85&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43 &#40;91&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time since onset of disease &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">8&#46;0&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;1&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;9&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&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="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Presence of erosions&#44; n &#40;&#37;&#41;</span>&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="\n
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                  \t\t\t\t">66 &#40;80&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;85&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;74&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Rheumatoid factor and&#47;or anti-CCP&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72 &#40;87&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;87&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;88&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Previous DMARD &#40;n&#41;</span>&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="\n
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                  \t\t\t\t">1&#46;0&#177;2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9&#177;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant DMARD&#44; n &#40;&#37;&#41;</span>&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;67&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;74&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;57&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;&#46;0001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46 &#40;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 &#40;61&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;48&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Leflunomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;9&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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Original Article
Reduction of Biological Agent Dose in Rheumatic Diseases: Descriptive Analysis of 153 Patients in Clinical Practice Conditions
Reducción de dosis de terapias biológicas en enfermedades reumáticas: análisis descriptivo de 153 pacientes en condiciones de práctica clínica
José Inciarte-Mundo, M. Victoria Hernández, Violeta Rosario, Virginia Ruiz-Esquide, Sonia Cabrera-Villalba, Julio Ramírez, Juan D. Cañete, Raimon Sanmartí
Corresponding author
sanmarti@clinic.cat

Corresponding author.
Unidad de Artritis, Servicio de Reumatología, Hospital Clínic de Barcelona, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Biological therapies are one of the most important advances in the treatment of various types of chronic arthritis and immune-mediated processes in recent decades&#46; Their clinical efficacy has been amply confirmed in I clinical trials and observational studies with an acceptable safety and tolerability profile&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Biological therapies include TNF antagonists &#40;infliximab&#44; etanercept&#44; adalimumab&#44; golimumab and certolizumab&#41; all with indications in rheumatoid arthritis &#40;RA&#41; and&#44; except certolizumab&#44; also approved for use in psoriatic arthritis &#40;PsA&#41; and ankylosing spondylitis &#40;AS&#41;&#46; In RA non-anti-TNF biologicals have also received approval&#44; such as abatacept&#44; rituximab and tocilizumab&#46; There are virtually no <span class="elsevierStyleItalic">head to head</span> studies between the various biological drugs&#44; but several meta-analyzes and systematic reviews show similar efficacy between them although some differences exist regarding their safety profile&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">With the introduction of these biological agents&#44; many patients who have been deemed DMARD refractory&#44; as in the case of RA or psoriatic arthritis&#44; or NSAIDs in the case of AS&#44; respond favorably and in a significant number there is a very good response&#44; even achieving a state of remission or low activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> These patients are initially treated with doses recommended by the data sheet according to the results of phase <span class="elsevierStyleSmallCaps">iii</span> clinical trials for product registration and approval by competent authorities&#44; but there is no consensus on what attitude to take in presence of sustained remission&#46; There are data in the literature that show that the abandonment of these therapies produces a clinical relapse of the disease in the majority of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> However&#44; some observational studies<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and recommendations by management guidelines for inflammatory arthritis such as RA<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> suggest the possibility of reducing the dose of biological agents in these patients to the lowest effective dose&#44; with the idea that some patients&#44; perhaps treated too intensively with standard doses&#44; could get the same benefit with a lower dose&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This dose reduction practice has been implemented empirically in recent years in the rheumatology practice&#44; partly to achieve cost reductions at a time of economic crisis&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In this cross-sectional study&#44; we present our experience with dose reduction in a group of patients with rheumatic diseases in clinical practice conditions&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This was designed as a descriptive&#44; cross-sectional and retrospective study&#44; which included some patients consecutively and for 6 months &#40;from June 2011 to November 2011&#41;&#44; all from an outpatient Arthritis Unit&#44; Rheumatology Department of a specialty hospital&#44; seen by a single investigator&#44; and who had received at least one dose of biological agent in 2011&#46; All the patients were treated according to the management guidelines of the Spanish Society of Rheumatology &#40;SER&#41; as per diagnosis&#46; The objective of the study was to analyze how many patients were receiving a reduced dose of biological agent at the time of analysis&#44; study their characteristics and compare them to the group of patients who continued with a standard dose&#46; A &#8220;low-dose&#8221; was defined as a treatment regimen with a reduced amount of drug than that recommended in the data sheet for each product&#44; either by using lower doses or by increasing intervals between dose administration&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The reduced dose regimen was established empirically&#44; on the basis of a suitable control and maintenance of a level of the activity of the disease &#40;in most cases remission according to activity rates and for &#8805;12 months&#41; performed by the rheumatologist who assessed patients in clinical practice conditions&#44; although not using any strategy or default protocol&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The patients in whom the drug was suspended due to adverse events were removed from the study&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Each of the patients included came for a check-up visit&#44; and data collection at the time of the analysis was performed and reviewed&#44; retrospectively&#44; through clinical history data&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">We analyzed the following variables&#58; <span class="elsevierStyleItalic">demographics</span> &#40;gender and age&#41;&#44; <span class="elsevierStyleItalic">diagnosis</span> years of evolution of the disease&#44; <span class="elsevierStyleItalic">previous treatment</span> &#40;synthetic and biological DMARDs&#41;&#44; <span class="elsevierStyleItalic">current biological treatment</span> &#40;type&#44; dose and duration of biological therapy&#41; and <span class="elsevierStyleItalic">current and concomitant treatment</span> &#40;synthetic DMARDs and&#47;or corticosteroids&#41;&#46; In patients diagnosed with RA we also determined serum ESR and CRP at the time of inclusion&#59; and calculated the <span class="elsevierStyleItalic">compound clinical activity index</span> DAS28 <span class="elsevierStyleItalic">at the time of analysis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In those patients receiving reduced biological doses at the time of analysis we studied&#58; 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using the Chi-square test for qualitative variables&#44; and Student&#39;s <span class="elsevierStyleItalic">t</span>-for quantitative variables&#46; Significance was set at <span class="elsevierStyleItalic">P</span>&#60;&#46;05&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">From June 2011 to November 2011 a total of 169 patients were initially included of whom some were excluded for not receiving the biological agent at the time of assessment &#40;n<span class="elsevierStyleMonospace">&#61;</span>2&#41; or because the treatment duration was less than 6 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>14&#41;&#46; Of the 153 patients included in the final analysis&#44; 63&#46;3&#37; were women and the average age was 51 years&#46; The main diagnosis was RA in 53&#46;5&#37; of patients&#46; Other diagnoses were&#58; EA &#40;18&#46;5&#37;&#41;&#44; PsA &#40;13&#46;5&#37;&#41; and miscellaneous &#40;14&#46;5&#37;&#41;&#44; including 8 juvenile idiopathic arthritis&#44; 3 undifferentiated spondyloarthropathy&#44; 3 seronegative polyarthritis&#44; 3 uveitis&#44; 2 palindromic rheumatism&#44; one mixed connectivetissue disease and one case of SAPHO syndrome and Still&#39;s disease&#46; Baseline characteristics of all patients examined&#44; as well as patients per group &#40;low and standard dose&#41; are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; At the time of analysis&#44; 70 patients &#40;45&#46;7&#37;&#41; received a reduced dose of biological either due to a decrease in dosage or an increase of the administration interval&#46; In none of the patients with reduced doses was a dose decreased due to adverse effects&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">25&#46;5&#37; of patients had previously received other biologic drugs&#44; with this circumstance being less frequent in the group of patients with reduced doses than in patients with standard doses&#44; although these differences did not reach statistical significance&#46; No differences were seen in the duration of the current biological therapy in both groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In most patients&#44; current biological therapy includes the anti-TNF drugs&#44; with no significant difference between the 2 groups&#46; In the group of patients with reduced dose&#44; the average time for such a reduction was 17&#46;4&#177;17&#46;5 months&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">When reduced dose patients were analyzed with respect to the biologic drug used&#44; 57&#46;6&#37; of those receiving adalimumab were receiving a reduced dose&#44; 54&#46;9&#37; of those taking etanercept&#44; 40&#37; of those receiving tocilizumab and 14&#46;3&#37; of patients treated with infliximab&#46; No dose reduction was seen in patients treated with other biologics&#46; The most employed reduced dose was 50<span class="elsevierStyleHsp" style=""></span>mg&#47;10 days etanercept &#40;48&#46;7&#37; of patients with reduced dose of etanercept&#41;&#44; 40<span class="elsevierStyleHsp" style=""></span>mg&#47;21 days for adalimumab &#40;78&#46;9&#37;&#41;&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;9 weeks for infliximab &#40;50&#37;&#41; and 6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4 weeks for tocilizumab &#40;87&#46;5&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; When we analyzed the group of patients with a reduced dose with regard to the underlying disease&#44; 50&#37; of those in the miscellaneous group had a reduced dose&#44; as well as 50&#37; of PsA&#44; 48&#46;2&#37; of patients with AS&#44; and 42&#46;6&#37; of RA&#46; 24 of the 83 patients receiving a standard dose &#40;28&#46;9&#37;&#41; had previously tried to reduce biologic drug dose without success&#44; having to return to the normal dose&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In patients diagnosed with RA no significant differences were seen in demographic characteristics&#44; duration of illness and duration of current biological therapy between the standard-dose group and low-dose group&#44; although in patients with a reduced dose the frequency of use NSAIDs and corticosteroids was significantly lower &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In RA patients there were no significant differences between patients with reduced doses and standard dose patients&#44; taking into account with patients with reduced dose having less concomitant use of DMARD and glucocorticoid compared to patients with standard doses &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; No differences were observed between groups regarding the duration of the disease&#46; When retrospectively analyzed&#44; values of disease activity at the time of the decision to reduce the dose were on average DAS28 2&#46;31&#177;0&#46;52&#44; whereas at the moment the data were collected it was 2&#46;32&#177;0&#46;72 &#40;no significant difference&#41;&#46; As expected when comparing the mean DAS28 between the low dose group and standard dose group&#44; significantly lower values were observed in the low dose group compared to the standard system&#46; Significant differences were also seen in the mean CRP and ESR values in both groups&#46; Similarly&#44; the percentage of patients in remission or low disease activity was significantly higher in the low dose group &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; In RA patients&#44; the reason for dose reduction was disease remission &#40;DAS28&#8804;2&#46;6&#41; in 32 patients &#40;91&#46;4&#37;&#41; and low activity &#40;DAS28 3&#46;2 and &#62;2&#46;6&#41; in 3 &#40;8&#46;6&#37;&#41;&#46; The mean time of dose reduction in these patients was 13&#46;6&#177;11&#46;9 months&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">In patients with reduced dose&#44; the therapeutic decision at the time of data collection was&#58; keep the dose reduced in 94&#46;3&#37; &#40;66 patients&#41;&#44; further reduce the dose of the drug in 3 patients &#40;4&#46;3&#37;&#41; and increase it in one patient &#40;1&#46;4&#37;&#41; according to the disease activity&#44; as assessed by clinical judgment and normal disease indexes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">In this study we analyze the frequency and characteristics of patients treated in our hospital who were being treated with low doses of biologics in clinical practice conditions&#44; having achieved adequate control of the disease&#44; comparing them with those receiving standard doses&#46; This transversal analysis confirms that a significant number of patients &#40;45&#46;7&#37;&#41; treated with biological drugs receive a reduced dose&#44; and the said dose is applied to various inflammatory arthritis&#44; and many such patients were receiving low doses for a relatively prolonged period of time &#40;mean 17 months&#41;&#44; maintaining remission or low disease activity&#46; There are differences between patients with reduced doses compared to standard-doses regarding concomitant use of DMARDs&#44; corticosteroids and NSAIDs&#46; In the case of RA and&#44; as expected&#44; lower dose patients showed a clear reduced disease activity and high rates of remission compared with patients with standard doses&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A clinical situations facing today&#39;s clinical rheumatologist is how to decide to follow the therapeutic approach in patients with adequate control of the disease under biological therapy&#44; remission or low activity extended in time&#46; Although most patients with RA and other inflammatory arthropathies are not in remission under these biological agents&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> there is no doubt that this goal&#44; or that of attaining a low disease activity&#44; can be achieved in a significant number of cases&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Biological drug withdrawal in these cases is followed&#44; in most cases&#44; of a clinical relapse within a few months&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> However&#44; observational studies of therapeutic strategy&#44; such as the BEST study demonstrate that the biological removal is possible in a high percentage of cases&#59; in this study&#44; more than half of the patients who had taken an initial strategy of infliximab plus methotrexate left infliximab after reaching low disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> However&#44; this possibility is more evident in those patients in whom the biological is administered as a first option&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> something unusual in the current strategy for RA treatment&#44; where the biological agent is virtually always used when one or more synthetic DMARD<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> have failed&#46; However&#44; such removal appears to be possible also in the case of RA in patients after failure to DMARDs&#44; as suggested by a Japanese study&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> although cases which would benefit from the removal would be those with little time since onset of RA&#44; but not those with a evolved disease as a new study by the Emery Group suggests&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Under this prism of high probability of clinical recurrence in patients who leave biological therapy once remission is achieved&#44; it sounds logical to take an intermediate position as would be the progressive dose reduction &#40;or increase in the dosing interval&#41; along with monitoring the disease activity&#46; In the current EULAR recommendations for the management of patients with RA<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> it is established that if a patient with RA achieves permanent remission &#40;12 months&#63;&#41; and is able to suspend steroids&#44; a strategy for biological dose reduction may be considered&#44; especially if the patient is being treated with DMARDs&#46; This recommendation&#44; based on expert opinion&#44; is being used empirically in clinical practice in different inflammatory arthropathies&#44; with some groups contributing their own experiences&#44; both in SA AR&#44;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;17&#8211;20</span></a> or<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> PsA with good results&#44; although some results have been obtained only through conference papers&#46; The SER&#44; in their consensus document on the use of biological therapies in RA<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> states that&#44; in patients who have achieved remission&#44; acceptable options are to maintain the biological agent&#44; try to lower the dose&#44; increase the dosing interval or even suspend the biological agent&#44; as long as the patient remains in clinical remission for a time yet to be defined&#46; However&#44; in the consensus document for PsA it is stated that there is no current evidence to recommend biological reduction in this disease&#44; although it can be considered individually&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In the case of AS&#44; the SER consensus postulates that in selected patients with minimal clinical activity such a reduction may be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The first description in the literature on the results of the reduction of the dose of biological agents in patients with arthritis dates back to 2002 when a Dutch group found that in a small group of patients with RA treated with adalimumab&#44; 76&#37; were able to reduce TNF antagonist doses&#44; with monitoring of the disease activity with DAS28&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The same group of authors stated in a recent editorial<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> that dose reduction is possible in patients with RA&#44; arguing that there is <span class="elsevierStyleItalic">overtreatment</span> in a significant number of patients in whom the dose may be reduced while achieving the same clinical benefit&#44; and in this sense monitoring of drug levels could be useful to the clinician&#46; These same authors also proved that in most patients with RA who had increased the dose of infliximab 3&#8211;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; a position with questionable evidence&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> the dose can be reduced to 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg without increasing disease activity as measured by DAS28&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">To the best of our knowledge only one randomized trial existed earlier which analyzes whether reduced biological dose can maintain control of the disease in patients who have achieved a low disease activity with standard biological dose&#46; The PRESERVE studied&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> RA patients with moderate activity as measured by DAS28&#44; who had achieved adequate control of RA &#40;DAS28<span class="elsevierStyleMonospace">&#60;</span>3&#46;2&#41; with standard doses of etanercept &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41; plus methotrexate and who were randomized to three treatment arms&#58; follow standard dose&#44; mid-dose &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41; and complete withdrawal and where then followed for one year&#46; Most patients still on etanercept maintained the low activity and no differences between those receiving a standard dose or reduced dose &#40;82&#46;6&#37; and 79&#46;1&#37; respectively&#41; was seen&#44; while in the patients who were withdrawn from the biological this percentage is significantly reduced &#40;42&#46;6&#37;&#41;&#46; Interestingly&#44; there are also differences in radiographic progression between the two groups of patients treated with etanercept&#46; In fact&#44; a French retrospective study showed a similar clinical response in patients with RA and AS when comparing &#8211; etanercept 25<span class="elsevierStyleHsp" style=""></span>mg 2 times&#47;week &#8211; with etanercept 25<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> However&#44; although the PRESERVE study is interesting and scientifically supports the strategy of etanercept dose reduction is possible in a significant number of patients with RA&#44; it must be remembered that the patients included had moderately active RA&#44; so these results cannot be extrapolated to patients who begin with high activity &#40;DAS28&#62;5&#46;1&#41;&#44; a circumstance which occurs for example in 62&#37; of RA patients in our service &#40;unpublished data&#41; or those starting other biological drugs&#46; It is unknown if there are similar studies in patients with PsA&#46; As for the SA or axial spondyloarthritis&#44; there is an ongoing national randomized study of dose reduction with TNF antagonists in 190 patients sponsored by the Spanish Foundation of Rheumatology and Spanish Society of Clinical Pharmacology &#40;REDES study&#41; that will undoubtedly provide data on this issue&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The reduced biological dose was used in this series in a similar percentage in the 4 groups of patients classified according to diagnosis&#44; though somewhat lower in patients with RA&#46; A recent study in patients with early disease who had gone into remission with adalimumab at a standard dose &#40;40<span class="elsevierStyleHsp" style=""></span>mg&#47;2 weeks&#41;&#44; points out that the ability to maintain this remission with increased dosing intervals &#40;adalimumab 40<span class="elsevierStyleHsp" style=""></span>mg&#47;4 weeks&#41; would be much more frequent in PsA than in RA<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#59; however&#44; it should be noted that our strategy of dose reduction in these diseases never contemplated the move to a monthly dose without first undergoing adalimumab treatment at a dose of 40<span class="elsevierStyleHsp" style=""></span>mg&#47;3 weeks&#46; Moreover&#44; it is interesting that in our study there were no differences in the time of disease progression or duration of current biological therapy between the groups with and without dose reduction&#44; although it was less frequent to see the use of prior biological agents in patients with dose reduction&#46; It is of interest&#44; in the case of RA&#44; to see the reduced use of concomitant DMARDs in patients with reduced doses&#44; a fact which certifies that patients with biological agents alone could also benefit from the reduction of dose&#46; As expected&#44; due to the decision to reduce the dose when the patient was in permanent clinical remission and occasionally in low activity&#44; reduced dose RA patients showed high remission rates&#44; lower disease activity and lower frequency of concomitant treatment with corticosteroids than patients with standard doses&#44; all data that would support the fact that such a reduction is possible in these patients to maintain adequate control of the disease&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The present study&#44; however&#44; has a number of limitations that should be mentioned&#46; First&#44; it is an observational study of clinical practice&#44; with a relatively small number of patients without any pre-established protocol&#44; so the decision and the moment to proceed with dose reduction are at the discretion of the investigator only&#46; Secondly&#44; the dose reducing regimen was also empirical and was done progressively&#44; while always taking into account the activity of the disease and&#44; in the case of clinical relapse&#44; returning to the standard dose and&#44; in fact&#44; a significant percentage of patients in this series had previously tried to reduce the dose&#44; but were back with the standard dose after the target had not been achieved&#59; we did not specifically examine predictors of recurrence in these patients&#46; Third&#44; it is a cross-sectional study&#44; so we do not know whether this reduction may or may not be sustained over time or result in a loss of clinical benefit in the medium to long term&#44; not only in terms of disease activity&#44; but also in functional capacity&#44; structural damage or even on the immunogenicity of these drugs&#46; However&#44; the fact that the average dose reduction in these patients was relatively prolonged &#40;17 months&#41; at the time of the evaluation and the fact that these patients remained in remission or low activity strongly suggests that such a reduction is possible in a number of patients followed in our clinical practice&#46; Fourth&#44; our experience with reduced biological dose is based primarily on etanercept&#44; adalimumab and tocilizumab and to a lesser extent&#44; infliximab&#46; We have no experience in terms of dose reduction&#44; for obvious reasons&#44; with other biological drugs such as golimumab or certolizumab&#44; nor with non-anti-TNF agents such as abatacept and rituximab&#46; In the latter case&#44; randomized trials with DMARD failing patients suggest a similar clinical efficacy between &#8211; a dose of 1<span class="elsevierStyleHsp" style=""></span>g &#40;2&#215;500<span class="elsevierStyleHsp" style=""></span>mg&#41; and 2<span class="elsevierStyleHsp" style=""></span>g &#40;2&#215;1000<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> In the recent EULAR 2012 meeting held in Berlin&#44; 2 studies examined rituximab dose reduction to 500<span class="elsevierStyleHsp" style=""></span>mg from the second cycle with conflicting results&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Finally&#44; we evaluated the incidence of adverse effects or costs associated with dose reduction&#46; Although it is unknown if dose reduction would achieve a significant reduction of adverse effects&#44; it is clear that it reduces costs&#44; at least in terms of direct costs and could be cost-effective&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> In fact&#44; we believe this strategy has allowed to greatly control expenditure on biologicals in our hospital&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In summary&#44; it is possible to reduce the dose of biological agents in patients with inflammatory arthritis in remission or low activity initially treated with standard doses&#44; achieving adequate control of the disease in many cases of routine clinical practice&#46; However&#44; there are virtually no studies designed to determine the effectiveness of dose reduction strategies&#44; so this practice is still empirical for clinical rheumatologist&#46; The publication of some studies&#44; and the strategies on dose reduction protocols are needed to support this clinical practice that is commonly used in many rheumatology services and&#44; possibly&#44; will be increased in the context of the current economic crisis and strict control of health spending&#46; It seems natural that&#44; in all the optimization strategies of the different drug treatment for inflammatory arthritis&#44; reducing the dose of biological agents should play a predominant role&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protection of people and animals</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that experiments have not been performed on humans or animals&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Data confidentiality</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Right to privacy and informed consent</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of patients and&#47;or subjects referred to in the article&#46; This document is in the possession of the corresponding author&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of Interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To analyze the frequency and characteristics of dose reduction of biological agents in a cohort of patients with chronic arthritis&#44; in clinical practice conditions in a tertiary level hospital&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Descriptive&#44; cross-sectional study&#44; which included all patients&#44; followed consecutively during 6 months &#40;June 2011&#8211;November 2011&#41;&#44; by one investigator&#44; with patients who at least have received one dose of biological agents in 2011&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We included 153 patients&#58; rheumatoid arthritis &#40;RA&#41; &#40;n<span class="elsevierStyleMonospace">&#61;</span>82&#41;&#44; ankylosing spondylitis &#40;n<span class="elsevierStyleMonospace">&#61;</span>29&#41;&#44; psoriatic arthritis &#40;n<span class="elsevierStyleMonospace">&#61;</span>20&#41;&#44; and miscellaneous group &#40;n<span class="elsevierStyleMonospace">&#61;</span>22&#41;&#46; Mean disease duration was 14&#46;9&#177;7&#46;7 years&#46; At the time of analysis&#44; 70 patients &#40;45&#46;7&#37;&#41; were receiving low doses of biological therapy &#40;50&#37; in miscellaneous group group&#44; 50&#37; in psoriatic arthritis&#44; 48&#46;2&#37; in ankylosing spondylitis&#44; and 42&#46;6&#37; in RA&#41;&#46; Mean time of dosage reduction was 17&#46;4&#177;17&#46;5 months&#46; The most common biological agents used in low dose were&#58; etanercept&#44; adalimumab and tocilizumab in 57&#46;6&#37;&#44; 54&#46;9&#37;&#44; and 40&#37; respectively&#44; in patients with a reduced dose of biological therapy&#46; The patients at low dose of biological therapy compared with standard dose had similar mean disease duration&#44; but received significantly less DMARDs&#44; glucocorticoids and NSAIDs&#44; and similar biological agent duration&#46; RA patients with reduced biological treatment&#44; at the time of analysis&#44; had higher remission rates versus patients receiving a standard dose &#40;82&#46;9&#37; vs 34&#37;&#44; <span class="elsevierStyleItalic">P</span>&#60;&#46;0001&#41;&#46; The medical decision at the time of analysis was to maintain low-dosage biological treatment in almost all patients&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In our clinical practice&#44; 45&#46;7&#37; of our chronic arthritis patients receive low dose of biological therapy&#44; after achieving remission or low activity at standard doses&#44; maintaining a good control of the disease&#46;</p>"
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      "es" => array:2 [
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Analizar la frecuencia y caracter&#237;sticas de la reducci&#243;n de dosis de f&#225;rmacos biol&#243;gicos en una cohorte de pacientes con artritis cr&#243;nica&#44; en condiciones de pr&#225;ctica cl&#237;nica de un hospital de tercer nivel&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo y transversal&#44; que incluy&#243; a todos los pacientes visitados consecutivamente durante 6 meses &#40;junio de 2011-noviembre de 2011&#41; por un solo investigador&#44; con pacientes que hab&#237;an recibido al menos una dosis de f&#225;rmaco biol&#243;gico durante el a&#241;o 2011&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 153 pacientes&#58; artritis reumatoide &#40;AR&#41; &#40;n<span class="elsevierStyleMonospace">&#61;</span>82&#41;&#44; espondilitis anquilosante &#40;n<span class="elsevierStyleMonospace">&#61;</span>29&#41;&#44; artritis psori&#225;sica &#40;n<span class="elsevierStyleMonospace">&#61;</span>20&#41; y grupo miscel&#225;nea &#40;n<span class="elsevierStyleMonospace">&#61;</span>22&#41; con una evoluci&#243;n media de 14&#44;9 &#177; 7&#44;7 a&#241;os&#46; En el momento del an&#225;lisis&#44; 70 pacientes &#40;45&#44;7&#37;&#41; estaba con dosis reducida &#40;un 50&#37; en el grupo miscel&#225;nea&#59; un 50&#37; en artritis psori&#225;sica&#59; un 48&#44;2&#37; en espondilitis anquilosante&#44; y un 42&#44;6&#37; en AR&#41;&#46; El tiempo medio de reducci&#243;n de dosis fue de 17&#44;4 &#177; 17&#44;5 meses&#46; Los f&#225;rmacos biol&#243;gicos m&#225;s utilizados a dosis reducidas fueron&#58; etanercept&#44; adalimumab y tocilizumab&#59; el 57&#44;6&#44; el 54&#44;9 y el 40 respectivamente de los pacientes tratados con estos agentes lo hac&#237;an a dosis reducidas&#46; Los pacientes con dosis reducidas en comparaci&#243;n con aquellos con dosis normales ten&#237;an un mismo tiempo de evoluci&#243;n de la enfermedad&#44; pero recib&#237;an menos FAME&#44; glucocorticoides y AINE&#44; con un tiempo similar de uso del agente biol&#243;gico&#46; Los pacientes con AR y dosis reducidas ten&#237;an&#44; en el momento del an&#225;lisis&#44; mayores &#237;ndices de remisi&#243;n que los pacientes con dosis normales &#40;82&#44;9 vs&#46; 34&#37;&#44; p &#60; 0&#44;0001&#41;&#46; La decisi&#243;n terap&#233;utica en el momento del an&#225;lisis fue mantener la dosis reducida en la pr&#225;ctica totalidad de los pacientes&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En nuestra pr&#225;ctica cl&#237;nica&#44; el 45&#44;7&#37; de los pacientes con artritis cr&#243;nica reciben terapia biol&#243;gica a dosis reducidas&#44; tras haber alcanzado la remisi&#243;n o baja actividad a dosis est&#225;ndares&#44; manteniendo la mayor&#237;a de ellos un buen control de la enfermedad&#46;</p>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9674;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Jos&#233; Inciarte-Mundo and M&#46; Victoria Hern&#225;ndez have participated equally in the design and elaboration of the study and manuscript&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Inciarte-Mundo J&#44; Hern&#225;ndez MV&#44; Rosario V&#44; Ruiz-Esquide V&#44; Cabrera-Villalba S&#44; Ram&#237;rez J&#44; et al&#46; Reducci&#243;n de dosis de terapias biol&#243;gicas en enfermedades reum&#225;ticas&#58; an&#225;lisis descriptivo de 153 pacientes en condiciones de pr&#225;ctica cl&#237;nica&#46; Reumatol Clin&#46; 2014&#59;10&#58;10&#8211;16&#46;</p>"
      ]
    ]
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">PsA&#58; psoriatic arthritis&#44; RA&#58; rheumatoid arthritis&#44; SA&#58; ankylosing spondylitis&#44; m&#58; months&#44; n&#58; number&#44; NS&#58; not significant&#44; TNF&#58; tumor necrosis factor&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">In bold&#44; statistically significant data&#46;</p>"
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            0 => array:2 [
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Total patients&#44; n<span class="elsevierStyleMonospace">&#61;</span>153&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with standard biological dose&#44; n<span class="elsevierStyleMonospace">&#61;</span>83&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with reduced biological dose&#44; n<span class="elsevierStyleMonospace">&#61;</span>70&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">49&#46;8&#177;15&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">63&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&#46;3&#177;14&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RA&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">NS&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="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">29 &#40;18&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PsA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;13&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;15&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#8805;2 <span class="elsevierStyleItalic">prior biological agents&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;13&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Previous&#44; n &#40;&#37;&#41;&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">39 &#40;25&#46;5&#41;&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">25 &#40;30&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-TNF&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;24&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Non-anti TNF&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="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time from start of biologic therapy &#40;m&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">55&#46;3&#177;38&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54&#46;9&#177;29&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Current biological</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-TNF&#44; n &#40;&#37;&#41;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">125 &#40;81&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">63 &#40;75&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62 &#40;88&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Non anti-TNF&#44; n &#40;&#37;&#41;&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">28 &#40;18&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20 &#40;24&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;11&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">8 &#40;11&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Patients With Reduced Doses&#58; Drugs and Doses Used&#46;</p>"
        ]
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">NSAIDs&#58; non-steroidal anti-inflammatory drugs&#44; DMARDs&#58; disease-modifying drug&#44; m&#58; months&#44; n&#58; number&#44; NS&#58; not significant&#44; TNF&#58; tumor necrosis factor&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">In bold&#44; statistically significant data&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Total non RA patients&#44; n<span class="elsevierStyleMonospace">&#61;</span>71&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with biological standard dose&#44; n&#61;36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with reduced biological dose&#44; n&#61;35&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#46;3&#177;12&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#46;1&#177;12&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;1&#177;14&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Gender &#40;female&#41;&#44; n &#40;&#37;&#41;</span>&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45 &#40;63&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21 &#40;58&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;68&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Time since onset of disease &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;0&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;1&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;9&#177;14&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant DMARD&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;25&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;27&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;22&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;16&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;13&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Leflunomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sulfasalazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant corticosteroids&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;15&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;22&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;&#46;0001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant NSAIDs&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;50&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;69&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;31&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Current biological therapy duration&#44; &#40;m&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;2&#177;30&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#177;36&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#177;29&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Current biological drug&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-TNF&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">67 &#40;94&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">33 &#40;91&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;97&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Non anti TNF&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Anti-CCP&#58; cyclic citrullinated peptide antibody&#59; DMARD&#58; disease-modifying anti-rheumatic drug&#44; m&#58; months&#44; n&#58; number&#44; NS&#58; not significant&#44; CRP&#58; C-reactive protein&#44; TNF&#58; tumor necrosis factor&#44; ESR&#44; erythrocyte sedimentation rate&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">In bold&#44; statistically significant data&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Total patients&#44; n&#61;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with biological standard dose&#44; n&#61;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients with reduced biological dose&#44; n<span class="elsevierStyleMonospace">&#61;</span>35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#46;1&#177;12&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#46;5&#177;11&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;5&#177;12&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Gender &#40;female&#41;&#44; n &#40;&#37;&#41;</span>&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">70 &#40;85&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43 &#40;91&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time since onset of disease &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">8&#46;0&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;1&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;9&#177;15&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Presence of erosions&#44; n &#40;&#37;&#41;</span>&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="\n
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                  \t\t\t\t">66 &#40;80&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;85&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;74&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Rheumatoid factor and&#47;or anti-CCP&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72 &#40;87&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;87&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;88&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Previous DMARD &#40;n&#41;</span>&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="\n
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                  \t\t\t\t">1&#46;0&#177;2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;0&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9&#177;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Concomitant DMARD&#44; n &#40;&#37;&#41;</span>&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;67&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;74&#46;4&#41;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;57&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;&#46;0001</span>&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate&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="\n
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                  \t\t\t\t">46 &#40;56&#41;&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">29 &#40;61&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">17 &#40;48&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Leflunomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;9&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;8&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sulfasalazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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Original language: English
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