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Are High Doses of Prednisone Necessary for Treatment of Interstitial Lung Disease in Systemic Sclerosis?
¿Son necesarias las dosis elevadas de prednisona para el tratamiento de la neumopatía intersticial en la esclerosis sistémica?
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Approximately 40% of patients develop moderate to severe restrictive lung disease, where the biggest decline in lung function occurs in the first 3–5 years since the onset of symptoms.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in this disease and has a very variable course, so the subgroup of patients who will develop into a rapid pulmonary<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> aggressive disease has not been identified.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Once interstitial fibrosis occurs, it is resistant to current treatment modalities, so it is very likely that aggressive therapy with immunosuppressive agents may be very effective at the beginning of the process.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The development of diagnostic methods such as computed tomography (CT) and bronchoalveolar lavage cytology allows for the identification of ILD in its first stages.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Several agents have been evaluated as treatment, but only oral or intravenous cyclophosphamide has proven effective. The results indicate that cyclophosphamide has modifying effects on lung function and response measures, such as dyspnea, quality of life, functional capacity and thickness of the skin.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> There is little evidence from studies evaluating the association between steroids and cyclophosphamide in the treatment of ILD. Pakas et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and Wanchu et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> report improvement in respiratory function with cyclophosphamide and high doses of prednisone, so we decided to evaluate whether the use of prednisone in high or low doses combined with intravenous cyclophosphamide is equally effective in the treatment of ILD in SS.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">We performed an exploratory, experimental and clinical study, randomized, single blind at the Ameijeiras Brothers Hospital during the period from September 2006 until December 2009. The study included 23 patients with ILD that met the criteria for classification of SS (ACR 1980)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and excluded patients with obstructive lung disease with VEF<span class="elsevierStyleInf">1</span>/capacity FVC (FVC)<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>70% than predicted, a history of occupational exposure and patients with disorders that affect lung function as IMA, congestive heart failure, severe valvular disease, emphysema and pulmonary hypertension.</p><p id="par0025" class="elsevierStylePara elsevierViewall">ILD was considered in patients with SS, the presence of a pattern of pulmonary ground glass or honeycombing on high resolution CT and/or the presence of active alveolitis in bronchoalveolar lavage fluid cell count with clinical dyspnea on exertion, accompanied by a decrease in FVC in the lung function test (LFT).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> This research protocol was approved by the scientific committee of the Hermanos Ameijeiras Hospital center of the Ministry of Health of the Republic of Cuba, and participants gave written agreement. Patients were randomized to two treatments. Each patient was enrolled consecutively, after assessing the above criteria, and was included in the study and was assigned to the corresponding treatment, with the help of a list of random numbers previously obtained by a computer using Asal. Two groups of patients were formed with different treatment regimens:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">–</span><p id="par0030" class="elsevierStylePara elsevierViewall">Group A, high doses (13 patients) were administered intravenous cyclophosphamide at a rate of 0.75<span class="elsevierStyleHsp" style=""></span>mg to 1<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> body surface area (maximum dose 1<span class="elsevierStyleHsp" style=""></span>g) monthly for 6 months and bimonthly the 6 remaining months, plus prednisone at 1<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>kg daily for 4 weeks and then decreasing the dose at 5<span class="elsevierStyleHsp" style=""></span>mg every 2 weeks until 10<span class="elsevierStyleHsp" style=""></span>mg.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">–</span><p id="par0035" class="elsevierStylePara elsevierViewall">Group B, low doses (10 patients) were administered the same cyclophosphamide dose and similarly to the first group, received combined oral prednisone 10<span class="elsevierStyleHsp" style=""></span>mg daily. For prevention of nausea and vomiting, ondansetron was administered (8<span class="elsevierStyleHsp" style=""></span>mg) plus intake of 3–4<span class="elsevierStyleHsp" style=""></span>l of water to prevent hemorrhagic cystitis.</p></li></ul></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Initial Assessment</span><p id="par0040" class="elsevierStylePara elsevierViewall">Complete clinical examination was performed, including measurement of the dyspnea index and the index of skin thickness (modified Rodnan). Patients were classified as diffuse and limited clinical skin forms using the LeRoy<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> extension.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Investigations: complete blood count, platelets, ESR, creatinine, glucose, AST, ALT, CPK, LDH, Addis 2<span class="elsevierStyleHsp" style=""></span>h, 24<span class="elsevierStyleHsp" style=""></span>h proteinuria, serology (VDRL), HIV, hepatitis C virus antibody, surface antigen, antinuclear antibodies (ANA<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>IF), echocardiogram, chest radiograph, RFT, CT, bronchoscopy and bronchoalveolar lavage cytology.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Blood count was performed 15 days after each pulse of cyclophosphamide, with dose adjustments when the leukocyte count <3<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Dyspnea was assessed using a Likert scale (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) 0–4 points grading from low to high degree of dyspnea: 0: none, 1: dyspnea on exertion after two flights of stairs, 2 dyspnea on exertion after a flight of stairs, 3 for dyspnea less than one flight of stairs or on the plain at their own pace, 4: dyspnea at rest.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">RFT was performed using an ERGOCID-plus computer. By performing spirometry, inspiratory and expiratory forced inspiratory volume were measured.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> A restrictive pattern was defined when there was a fall in FVC<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>80%.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Intensity: considered mild (79%–65%), moderate (64%–49%). severe (48%–35%) and severe (<34%).</p><p id="par0070" class="elsevierStylePara elsevierViewall">Lung CTs was performed on a multislice CT scanner with 40 channels for multiplanal reconstruction, with 0.1<span class="elsevierStyleHsp" style=""></span>mm slices. This study revealed the presence of two patterns, abnormal and the normal pattern. ILD was demonstrated by the presence of two patterns of abnormal appearance (“ground glass” and “honeycomb”).<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The “ground glass” appearance was defined by an increased density of the lung parenchyma, a fine reticular pattern of curvilinear opacities which are radio transparent spaces between 1 and 2<span class="elsevierStyleHsp" style=""></span>mm in diameter. The presence of ground-glass opacities in the posterior basal subpleural courts was searched for in the prone position to exclude the possibility of gravitational effects that cause increased parenchymal density. The second pattern that looks like a honeycomb lattice medium was defined as subpleural lines, thickened septal or subpleural parenchymal borders and air space having a diameter between 3 and 10<span class="elsevierStyleHsp" style=""></span>mm.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Readings and semiquantitative assessment of pulmonary radiological deterioration were made using the Warrick<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> index and performed by two radiologists; any difference in interpretation was resolved by consensus. Elemental lesions were considered when the scores from one to 5 according to the severity were 1, ground glass opacities; 2, pleural irregularities in the edges; 3, lines by septal thickening and subpleural interlobular septa (1 thickening linear cm of the pleura), 4, honeycomb, and 5, subpleural cystic areas of wall thickening.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Also, Warrick's score assigns values between 1 and 3 according to the number of segments affected by the type of injury. A score of 1 indicates that the lesion is present in 1–3 segments; a score of 2 is present in 4–9 segments, and score 3 lesions are present in more than 9 segments. The scores for severity and extent of injury were added to provide a total CT score ranging from 0 to 30.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Bronchoscopy and washing cytology: the percentage of polymorphonuclear leukocytes<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>3% and the percentage of eosinophils<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>2% were considered pathological; therefore those were considered as an active<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> bronchoalveolar lavage.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Clinical evaluation was performed and a blood count with differential was performed each month before administering cyclophosphamide.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Final assessment: at the end of treatment we performed a thorough clinical examination, including measurement of the levels of dyspnea and skin thickness, hematological tests, echocardiogram, chest radiograph, RFT, CT, bronchoscopy and cytological lavage. Two patients were not evaluated after they dropped out.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical Data Analysis</span><p id="par0105" class="elsevierStylePara elsevierViewall">The collected data were processed using SPSS Vs11.5. Descriptive statistics were used for qualitative variables (absolute and relative frequencies) and for quantitative variables (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>or standard deviation). To determine the homogeneous distribution of the two groups in baseline conditions, we used a homogeneity test statistic such as the chi-square, and the use of nonparametric Mann–Whitney test was used to calculate the average difference between the two groups for the duration of the disease. We also used the Wilcoxon test for related samples to evaluate the change in lung expansion obtained after treatment by Warrick index.</p><p id="par0110" class="elsevierStylePara elsevierViewall">We considered a group of key variables after treatment analyzed in each group and compared to each other using the nonparametric Mann–Whitney tests.</p><p id="par0115" class="elsevierStylePara elsevierViewall">In all statistical tests employed we considered a significance level of 0.05.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0120" class="elsevierStylePara elsevierViewall">In <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, shows the baseline characteristics of both groups: group A was composed of 10 patients, all women, with a duration of disease of 61.6 months, 8 with a diffuse clinical form and 2 limited. We obtained a 3.5-dyspnea index and skin thickness of 20.5; there was a predominance of active bronchoalveolar lavages. This group had a lower mean value of FVC, more patients with a honeycomb pattern and a higher Warrick score compared with group B. Total patients with positive ANA were 7. In group B, 13 patients, all women, and a time of disease progression of 67.2 months, 9 were of the diffuse clinical form and 4 of the limited, with a predominantly ground glass pattern on CT and active bronchoalveolar lavage, and a rate of dyspnea and a skin thickness of 3.1 and 16.8, respectively, with ANA-positive in 9 patients. One patient in each group did not complete the study. In group A one patient died due to pulmonary thromboembolism after completing one month of treatment, and in group B one patient was discontinued because she developed hemolytic anemia after the third month of treatment. None of the causes of abandonment was attributed to treatment.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Response to Treatment</span><p id="par0125" class="elsevierStylePara elsevierViewall">In the low dose group we evidenced an improvement in the radiological lesions and the Warrick index, with the high dose group differing, with a slight worsening of Warrick performance and no changes in radiological lesions (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">The clinical variables, the dyspnea index and improvement in skin thickness changes were seen in both groups, just as bronchoalveolar lavage and forced vital capacity. None of them showed significant differences between groups (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">Both groups had similar minor adverse reactions (nausea and vomiting) that were resolved with the administration of antiemetics.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0140" class="elsevierStylePara elsevierViewall">We determined the effectiveness of high or low dose of cyclophosphamide associated with prednisone in the treatment of ILD in the course of SS. A search of the literature provides very few studies specifically performed to review this association. There are many papers which evaluate the efficacy of cyclophosphamide and, to a lesser extent, the use of cyclophosphamide and steroids, rarely comparing the efficacy of cyclophosphamide with high or low dose of prednisone, as performed by Pakas et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Of the 23 patients with ILD, 73% are of the diffuse clinical form and 27% were limited. The presence of ILD is reported in up to 90% of the diffuse form and associated with the presence of SCL-70<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> antibodies. The limited form usually has an indolent course with a predominance of vascular involvement, but in patients with prolonged illness and dyspnea can lead to lung disease,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> which is evident in the group of low-dose prednisone. Of the 13 patients included, there are only 4 with the limited clinical form, but have dyspnea as the main symptom and a longer history of disease.</p><p id="par0145" class="elsevierStylePara elsevierViewall">ANA positivity was around 70%, a value lower than that reported in other regions, reflecting its presence in 90%–95%.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> We think that the method used (immunofluorescence and rat liver substrate) may be related to these results, although a recent study in our geographic area, Puerto Rico, displays ANA positivity in 66.7% of patients.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> A limitation of the study is absence of specific autoantibodies related to lung disease.</p><p id="par0150" class="elsevierStylePara elsevierViewall">CT patterns in group A showed no regression and motivated primarily because this group included more patients with a honeycomb pattern corresponding to established lung fibrosis, where the response to treatment is lower. With these elements, group A shows a greater severity, yet, when we tried to strike a balance between groups by random assignment of patients, it was seen as weak and foreign to our purpose. In contrast, in group B there was regression of lesions in 50% which does not correspond to what has been achieved by Pakas et al. in those who were in the group of high dose steroids. The course of systemic sclerosis is characterized by parenchymal lung injury followed by inflammation and subsequent fibrosis.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The initial inflammation corresponds to a ground glass pattern on CT and active alveolitis on bronchoalveolar lavage identifying an inflammatory stage is this the right time to start immunosuppressive<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> therapy. In the high dose patients there was a higher percentage of mean reticular involvement that corresponds to the fibrosis seen on histological examination, which is considered the reason for the worsening of the Warrick index. Patients with this impairment have a greater restriction of lung function, however, both groups showed improvement in FVC in the same range. Although not directly related to the study variables and FVC Warrick index, it was found that patients in group A have a higher average value in the Warrick index and small FVC relative to group B. This inverse relationship is due to the predominance of honeycomb pattern in group A, which increases the index score (by greater severity and extent of lung injury), with the consequent decrease in the mean value of FVC and development of restrictive lung disease. In group B, a lower index value associated with the presence of a ground glass pattern, mainly on the lung bases and periphery, provides a lower score for the severity and extent of injuries, and expresses a lower impairment of FVC. A restrictive pattern is associated with severe dyspnea, anti-SCL-70 and the development of lung fibrosis.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> We believe that more data is needed to confirm that these changes are clinically significant in the long-term natural history of lung disease and show that progression of the disease is indolent, but with considerable individual variability.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Clinical improvement was found in both groups to assess dyspnea and showed similar results to those obtained by Pakas et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> for patients receiving high-dose cyclophosphamide and prednisone. In the Scleroderma Lung Study, a placebo-controlled, randomized double-blind trial that evaluated oral cyclophosphamide for a year, they found a similar beneficial effect on dyspnea in the group treated with cyclophosphamide.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Both groups improved the FVC, but it was not possible to measure the diffusion capacity of carbon monoxide (DCLO). We consider this a weakness of the study. The increase in FVC above 4% in the present study is higher than reported by Simeon Aznar,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> which used pulse cyclophosphamide for 2 years and low doses of steroids. Similar results were achieved Pakas et al. in the group of high-dose prednisone. No improvement in FVC achieved clinical significance as defined by an improvement of at least 10% of the predicted value of each measurement.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Both groups experienced improvement in the cell count of bronchoalveolar lavage after completion of treatment. The diagnosis in about 9% was of alveolitis in patients with a normal CT, close to the 10%–15% found by other authors.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> An increased percentage of neutrophils in the lavage cytology has been associated with more extensive lung disease on CT, a greater reduction in DLCO and early mortality.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The group of low-dose prednisone is useful in the treatment of active forms of ILD, with a good safety profile and lower risk of complications secondary to the use of high doses of prednisone, such as osteoporosis, osteonecrosis, immunosuppression or the development of scleroderma renal crisis.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Although it was not the objective of this study, we evaluated the rate of skin thickness, which shows significant improvement in both groups. A similar result was obtained by Pakas et al., but only with the group of high doses of steroids. This decrease in skin thickness has been found in other studies, where the indication of cyclophosphamide was not directly related to skin involvement. However, a study by Andrade Macedo<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> in Brazil, showed that the clinical form in patients with diffuse and severe skin thickening without visceral involvement had a satisfactory response to cyclophosphamide.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Unlike the results obtained by Pakas et al., our research showed that both treatment groups were favored, successful and with a good safety profile for the treatment of lung and skin involvement in systemic sclerosis. We concluded that a combination of low doses of steroids with cyclophosphamide is effective in treating ILD especially in active forms. The results show no differences from the high dose group, but the sample size and the more severe progression of patients with high doses require further studies to confirm this data.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors have no disclosures to make.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres125735" "titulo" => array:6 [ 0 => "Abstract" 1 => "Introduction" 2 => "Objectives" 3 => "Method" 4 => "Results" 5 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec113027" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres125736" "titulo" => array:6 [ 0 => "Resumen" 1 => "Introducción" 2 => "Objetivos" 3 => "Método" 4 => "Resultados" 5 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec113026" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Initial Assessment" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Statistical Data Analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Response to Treatment" ] ] ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-05-25" "fechaAceptado" => "2011-11-12" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec113027" "palabras" => array:4 [ 0 => "Cyclophosphamide" 1 => "High and low doses of prednisone" 2 => "Interstitial lung disease" 3 => "Systemic sclerosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec113026" "palabras" => array:4 [ 0 => "Ciclofosfamida" 1 => "Dosis alta y baja de prednisona" 2 => "Esclerosis sistémica" 3 => "Neumopatía intersticial" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Interstitial lung disease (ILD) as part of systemic sclerosis (SS) is a leading cause of morbidity and mortality.</p> <span class="elsevierStyleSectionTitle">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To evaluate the use of intravenous pulse cyclophosphamide combined with low and high doses of prednisone in the treatment of ILD in SS is equally effective.</p> <span class="elsevierStyleSectionTitle">Method</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">An experimental, exploratory and randomized single-blind clinical trial was conducted at Hermanos Ameijeiras Clinical Surgical Hospital from September 2006 to December 2009, including 23 patients with SS and ILD. Two treatment schedules were evaluated and randomly assigned. Group A was composed of 13 patients with a monthly dose of cyclophosphamide (ev) for 6 months and a twice-monthly dose for the remaining 6 months, prednisone (1<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>kg<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>day) 4 weeks and then the dose was lowered to 5<span class="elsevierStyleHsp" style=""></span>mg every 2 weeks up to 10<span class="elsevierStyleHsp" style=""></span>mg. Group B: 10 patients with cyclophosphamide (ev), oral prednisone 10<span class="elsevierStyleHsp" style=""></span>mg daily.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There are significant differences at onset of CVF and the honeycomb pattern between both groups, where the high dose group was at a disadvantage. At the end of treatment the low dose group achieved improvement of radiologic lesions and the Warrick index, unlike the high dose group. The remaining variables experienced improvement in both groups without marked inequality. Similarly, slight adverse reactions were present in both groups. Two patients dropped out of the study.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A combination of low dose steroids with cyclophosphamide is effective in interstitial lung disease treatment especially in active disease, and results did not show differences regarding the high dose group but the sample size and the evolutionary severity of high dose patients oblige other studies to verify these data.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Introducción</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La neumopatía intersticial (NI) en el curso de la esclerosis sistémica (ES) constituye la causa principal de morbilidad y mortalidad.</p> <span class="elsevierStyleSectionTitle">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar si el uso de prednisona en altas o bajas dosis combinado con ciclofosfamida intravenosa (iv) resulta igualmente eficaz en el tratamiento de la NI en la ES.</p> <span class="elsevierStyleSectionTitle">Método</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se realizó un estudio explicativo experimental tipo ensayo clínico, aleatorizado y a simple ciego, donde se reclutó a 23 pacientes con ES y NI. Se evaluaron dos esquemas de tratamientos; grupo A: 13 pacientes con ciclofosfamida (iv) mensual durante 6 meses y bimensual durante los 6 meses restantes, prednisona (1<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>kg<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>día) 4 semanas y después se rebajó la dosis a 5<span class="elsevierStyleHsp" style=""></span>mg cada 2 semanas hasta 10<span class="elsevierStyleHsp" style=""></span>mg, y grupo B: 10 pacientes con ciclofosfamida (iv) y prednisona por vía oral 10<span class="elsevierStyleHsp" style=""></span>mg diaria.</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se muestran las diferencias significativas al inicio del estudio en la CVF y el patrón en panal de abejas entre ambos grupos, resultando desfavorecido el grupo de dosis altas. Al concluir el tratamiento, el grupo de bajas dosis logró una mejoría de las lesiones radiológicas y del índice de Warrick, a diferencia del grupo de dosis altas. Las restantes variables experimentaron mejoría en los dos grupos, sin marcada desigualdad. Se presentaron de forma similar reacciones adversas ligeras. Dos pacientes abandonaron la investigación.</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Una combinación de dosis bajas de esteroides con ciclofosfamida es eficaz en el tratamiento NI especialmente en las formas activas. Los resultados no muestran diferencias respecto al grupo con altas dosis, pero el tamaño muestral y la mayor gravedad evolutiva de los pacientes con altas dosis, obligan a otros estudios para confirmar estos datos.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please, cite this article as: Pérez Campos D, et al. ¿ Son necesarias las dosis elevadas de prednisona para el tratamiento de la neumopatía intersticial en la esclerosis sistémica? Reumatol Clin. 2012;<span class="elsevierStyleBold">8(2)</span>:58–62.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Maximum score: 51 units.</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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">4 level scale</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">Level 0: normal skin. \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">Level 1: Thickened skin. \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">Level 2: Skin thickening, no pinching possible. \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">Level 3: Skin thickening with no movement. \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="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 " rowspan="2" align="left" valign="middle">Anatomical areas: 17</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">Central zones: face, anterior surface of the thorax and abdomen. \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">Bilateral zones: fingers, back of the hands, forearms, arms, thighs, legs, back of the feet. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212221.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Skin Thickness Index (Modified Rodnan).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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 \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">High dosesn<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10 \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Low dosesn<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>13 \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Duration of disease (mean months)</span> \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">61.6 \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">67.2 \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">.75 \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="4" 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">Clinical forms</span> \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"> \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"> \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">.55 \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>Limited \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">2 \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">4 \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"> \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>Diffuse \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">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \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"> \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="4" 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">Dyspnea index (mean)</span> \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">3.5 \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">3.1 \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">.17 \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">Skin thickness index (mean)</span> \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">20.5 \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">18.6 \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">.19 \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">FVC (mean)</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67.7 \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">.03 \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="4" 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">CT scan</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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"> \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">.13 \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>Normal \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 \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 \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"> \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>Ground glass \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">2 \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">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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>Honeycomb \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">7 \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">4 \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"> \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="4" 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">Warrick index (mean)</span> \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">9.4 \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">4.3 \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">.015 \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="4" 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">Broncoalveolar lavage</span> \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"> \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"> \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">.55 \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>Active \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">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \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"> \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>Passive \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">2 \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">4 \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"> \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="4" 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">Positive antinuclear antibody</span> \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">7 \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">9 \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">.96 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212218.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara">Forced vital capacity.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara">Tomographic patterns.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">General Initial Characteristics.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">One patient in group A (ground glass pattern) and a patient in group B (honeycomb pattern) did not finish the study.</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 \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">Patterns \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 " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">High dose (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9)</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Low dose (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>12)</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Onset \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">After<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Onset \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">After<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Ground glass \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 \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 \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 \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 \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">Reticular (Honeycomb) \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 \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 \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 \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 \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">Negative \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 \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 \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 \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 \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">WARRICK Index (mean<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> and SD) \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">9.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.3 \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">9.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.5 \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">4.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.0 \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">P</span> \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 " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.32</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.76</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212219.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara">After one year of treatment.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Behavior of the Patterns of Lung Affection and the Warrick Tomographic Index.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Mann–Whitney's non-parametric test was employed.</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 \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">Main variables \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">High dosesn<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9n<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>DE \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Low dosesn<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>12n<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>DE \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Dyspnea index \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">1.22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.67 \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">0.92<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.67 \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">.51 \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">Forced vital capacity \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">57.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15.3 \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">71.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>17.5 \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">.06 \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">Broncoalveolar lavage \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">13.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>18.7 \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">9.50<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.2 \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">.75 \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">Skin thickness index \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">13.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.3 \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">12.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.75 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212220.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Main Variables Measured After Treatment.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe restrictive lung disease in systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "V.D. Steen" 1 => "C. Conte" 2 => "G.R. Owens" 3 => "T.A. Medsger Jr." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1994" "volumen" => "37" "paginaInicial" => "1283" "paginaFinal" => "1289" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7945490" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The lung in systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "V. Steen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Clin Rheumatol" "fecha" => "2005" "volumen" => "11" "paginaInicial" => "40" "paginaFinal" => "46" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16357695" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mortality in systemic sclerosis: an international meta-analysis of individual patient data" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.P.A. Ioannidis" 1 => "P.G. Vlachoyannopoulos" 2 => "A.B. Haldich" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.amjmed.2004.04.031" "Revista" => array:7 [ "tituloSerie" => "Am J Med" "fecha" => "2005" "volumen" => "118" "paginaInicial" => "2" "paginaFinal" => "10" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15639201" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109799002120" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Scleroderma clinical problems the lungs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 25 | 19 | 44 |
| 2024 October | 81 | 36 | 117 |
| 2024 September | 131 | 27 | 158 |
| 2024 August | 148 | 47 | 195 |
| 2024 July | 174 | 48 | 222 |
| 2024 June | 130 | 36 | 166 |
| 2024 May | 108 | 36 | 144 |
| 2024 April | 109 | 58 | 167 |
| 2024 March | 136 | 37 | 173 |
| 2024 February | 88 | 48 | 136 |
| 2024 January | 108 | 30 | 138 |
| 2023 December | 107 | 30 | 137 |
| 2023 November | 81 | 47 | 128 |
| 2023 October | 164 | 39 | 203 |
| 2023 September | 153 | 43 | 196 |
| 2023 August | 82 | 19 | 101 |
| 2023 July | 88 | 33 | 121 |
| 2023 June | 68 | 38 | 106 |
| 2023 May | 80 | 21 | 101 |
| 2023 April | 91 | 12 | 103 |
| 2023 March | 159 | 26 | 185 |
| 2023 February | 129 | 39 | 168 |
| 2023 January | 241 | 22 | 263 |
| 2022 December | 148 | 46 | 194 |
| 2022 November | 128 | 43 | 171 |
| 2022 October | 149 | 32 | 181 |
| 2022 September | 126 | 42 | 168 |
| 2022 August | 115 | 40 | 155 |
| 2022 July | 89 | 45 | 134 |
| 2022 June | 90 | 38 | 128 |
| 2022 May | 88 | 57 | 145 |
| 2022 April | 120 | 46 | 166 |
| 2022 March | 148 | 55 | 203 |
| 2022 February | 172 | 50 | 222 |
| 2022 January | 137 | 60 | 197 |
| 2021 December | 125 | 38 | 163 |
| 2021 November | 148 | 58 | 206 |
| 2021 October | 150 | 76 | 226 |
| 2021 September | 135 | 45 | 180 |
| 2021 August | 157 | 41 | 198 |
| 2021 July | 139 | 37 | 176 |
| 2021 June | 173 | 38 | 211 |
| 2021 May | 143 | 54 | 197 |
| 2021 April | 456 | 107 | 563 |
| 2021 March | 265 | 44 | 309 |
| 2021 February | 217 | 39 | 256 |
| 2021 January | 172 | 26 | 198 |
| 2020 December | 158 | 32 | 190 |
| 2020 November | 137 | 30 | 167 |
| 2020 October | 134 | 31 | 165 |
| 2020 September | 125 | 41 | 166 |
| 2020 August | 107 | 33 | 140 |
| 2020 July | 103 | 41 | 144 |
| 2020 June | 98 | 29 | 127 |
| 2020 May | 77 | 32 | 109 |
| 2020 April | 99 | 21 | 120 |
| 2020 March | 28 | 12 | 40 |
| 2020 February | 1 | 0 | 1 |
| 2019 January | 1 | 0 | 1 |
| 2018 May | 7 | 0 | 7 |
| 2018 April | 62 | 11 | 73 |
| 2018 March | 91 | 8 | 99 |
| 2018 February | 75 | 1 | 76 |
| 2018 January | 66 | 10 | 76 |
| 2017 December | 62 | 6 | 68 |
| 2017 November | 83 | 6 | 89 |
| 2017 October | 85 | 3 | 88 |
| 2017 September | 57 | 22 | 79 |
| 2017 August | 69 | 6 | 75 |
| 2017 July | 62 | 8 | 70 |
| 2017 June | 67 | 9 | 76 |
| 2017 May | 109 | 12 | 121 |
| 2017 April | 66 | 8 | 74 |
| 2017 March | 66 | 4 | 70 |
| 2017 February | 177 | 13 | 190 |
| 2017 January | 92 | 5 | 97 |
| 2016 December | 114 | 16 | 130 |
| 2016 November | 112 | 5 | 117 |
| 2016 October | 148 | 8 | 156 |
| 2016 September | 240 | 11 | 251 |
| 2016 August | 141 | 11 | 152 |
| 2016 July | 75 | 11 | 86 |
| 2015 December | 2 | 0 | 2 |
| 2015 September | 1 | 26 | 27 |
| 2015 August | 7 | 0 | 7 |
| 2015 July | 54 | 8 | 62 |
| 2015 June | 96 | 7 | 103 |
| 2015 May | 128 | 15 | 143 |
| 2015 April | 111 | 13 | 124 |
| 2015 March | 124 | 7 | 131 |
| 2015 February | 112 | 12 | 124 |
| 2015 January | 116 | 10 | 126 |
| 2014 December | 113 | 12 | 125 |
| 2014 November | 105 | 11 | 116 |
| 2014 October | 121 | 15 | 136 |
| 2014 September | 69 | 5 | 74 |
| 2014 August | 89 | 17 | 106 |
| 2014 July | 94 | 14 | 108 |
| 2014 June | 98 | 17 | 115 |
| 2014 May | 98 | 15 | 113 |
| 2014 April | 75 | 11 | 86 |
| 2014 March | 81 | 19 | 100 |
| 2014 February | 53 | 20 | 73 |
| 2014 January | 66 | 24 | 90 |
| 2013 December | 67 | 7 | 74 |
| 2013 November | 52 | 17 | 69 |
| 2013 October | 78 | 12 | 90 |
| 2013 September | 70 | 19 | 89 |
| 2013 August | 93 | 22 | 115 |
| 2013 July | 86 | 18 | 104 |
| 2013 June | 62 | 18 | 80 |
| 2013 May | 79 | 39 | 118 |
| 2013 April | 57 | 32 | 89 |
| 2013 March | 62 | 25 | 87 |
| 2013 February | 45 | 24 | 69 |
| 2013 January | 39 | 24 | 63 |
| 2012 December | 47 | 26 | 73 |
| 2012 November | 36 | 17 | 53 |
| 2012 October | 26 | 29 | 55 |
| 2012 September | 14 | 5 | 19 |
| 2012 July | 4 | 0 | 4 |
| 2012 June | 8 | 0 | 8 |
| 2012 May | 19 | 0 | 19 |
| 2012 April | 19 | 0 | 19 |
Show all
