Severe Infections in Patients With Autoimmune Diseases Treated With Cyclophosphamide

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Cavallasca, Cecilia A. Costa, Maria del Rosario Maliandi, Liliana E. Contini, Elena Fernandez de Carrera, Jorge L. Musuruana" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Javier A." "apellidos" => "Cavallasca" "email" => array:1 [ 0 => "jcavallasca@yahoo.com.ar" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Cecilia A." "apellidos" => "Costa" ] 2 => array:2 [ "nombre" => "Maria del Rosario" "apellidos" => "Maliandi" ] 3 => array:2 [ "nombre" => "Liliana E." "apellidos" => "Contini" ] 4 => array:2 [ "nombre" => "Elena" "apellidos" => "Fernandez de Carrera" ] 5 => array:2 [ "nombre" => "Jorge L." "apellidos" => "Musuruana" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Sección Reumatología y Enfermedades Autoinmunes Sistémicas, Hospital J.B. Iturraspe, Santa Fe, Argentina" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Infecciones graves en pacientes con enfermedades autoinmunes tratados con ciclofosfamida" ] ] "textoCompleto" => "IntroductionSystemic autoimmune diseases are a heterogeneous group of disorders in which immune system dysfunction plays a central role, and with infections a major cause of morbidity and mortality in these patients. Among the predisposing factors for this complication, genetic, immunological abnormalities, different organ systems affected, disease activity and drug use, among which are corticosteroids and immunosuppressants, such as cyclophosphamide (CF), stand out.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>CF is an alkylating agent with potent antiproliferative action on T and B lymphocytes, used in the most severe forms of rheumatic diseases, particularly systemic lupus erythematosus (SLE) and ANCA-associated vasculitis; it has contributed to improved survival in these patients. However, its use is associated with bone marrow suppression, bladder toxicity, increased risk of malignancies, infertility and infections.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>The objective of this study was to determine the percentage of patients with systemic autoimmune diseases, in treatment with CF, who had developed serious infections.Severe infection was defined as an event caused by the herpes zoster or that which merited hospitalization and/or intravenous antibiotic therapy; it also considered its relationship with the type of rheumatic disease and the cumulative dose of CF and corticosteroids.Materials and MethodsThe medical records of 60 patients with systemic autoimmune diseases seen at the Rheumatology and Systemic Autoimmune Diseases Section of the Hospital Iturraspe JB in Santa Fe, Argentina, who were treated with CF between November 1996 and March 2011, were retrospectively reviewed. Demographics of each patient, the reason for using CF, concomitant steroid use, cumulative dose of CF and corticosteroids, infection, need for hospitalization and/or antibiotics/antivirals were analyzed.Statistical AnalysisAn observational, retrospective and cross-sectional analysis was performed. Position summary measures were calculated: mean and median, as well as dispersion measures such as standard deviation, ranges and their respective 95% confidence intervals (CI). Risks were estimated by odds ratio (OR) (the variables analyzed were gender, age, cumulative dose of steroids and CF) and the corresponding CI. The nonparametric Mann–Whitney test was used for comparison of means and Fisher's exact test for independence. A significance level of alpha=0.05 was adopted. SPSS 18.0 and Epi Info 2000<a class="elsevierStyleCrossRef" href="#bib0015">3</a> software packages were used for analysis.ResultsThe study included 60 patients, 48 women and 12 men; mean age±standard deviation thereof was 42.83±14.12 years.The most common pathology was SLE (n=37), followed by systemic vasculitis (n=8), systemic sclerosis (n=6), overlap syndromes (n=4), rheumatoid arthritis (n=2), relapsing polychondritis (n=1), cutaneous vasculitis (n=1) and retinal vasculitis (n=1).The presence of diffuse proliferative glomerulonephritis (DPGN) in 28 cases was the main indication for the use of CF, which represented 47% of cases.In total, 541 boluses were applied, the doses of each varying from 500mg to 1g.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> The cumulative dose of CF ranged from 1.0 to 166.5g, with a median of 7.3g. There were 5 patients who received 25g or more of CF, values considered statistically atypical for this sample, of which one (cumulative dose =102g) had an infectious process.In the case of steroids, the median of the cumulative dose was 17.3g, with a range of 3.0–91.0g. In this case there were 4 patients with cumulative doses higher than 54.0g, one of which (cumulative dose 69.7g) presented infection.It should be noted that patients with cumulative doses of CF considered atypical are not the same as those that had high cumulative doses of corticosteroids.During follow-up, 2 patients with severe forms of granulomatosis with polyangiitis (Wegener's granulomatosis [WG]) received oral CF for a time.15% of patients (n=9) had at least one infectious episode during treatment with CF. The most frequent infections were community acquired pneumonia (CAP), 3 cases (33%) and herpes zoster, 2 cases (22%) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). A single case presented leucopenia with neutropenia at time of infection. None of the patients died as a result of the infectious process. The time from the start of treatment with CF and infectious symptoms ranged between 2 and 66 months.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>When comparing the group of patients who were infected with those who were not, no statistically significant differences regarding age (P=0.534), gender (P=0.675) and cumulative dose of CF were found at the time of infection (P=0.283) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>When analyzing the cumulative dose of steroids and comparing them between patients with and without infection, it was observed that all patients who developed infections had a cumulative dose between 15.0 and 69.6g, while those in which there was no infectious process, the dose ranged between 3.0 and 90.6g. Furthermore, in 50% of patients without infection the accumulated dose was 16.0g or less.Cumulative corticosteroid doses in patients with and without infection were compared, finding significant differences (P=0.007).A cutoff was established in the cumulative steroid doses of 20.0g, which coincided with the 75th percentile of the dose values of patients who were not infected .A statistically significant association between high levels of cumulative dose of steroids and infection (P=0.029) was found, which would indicate that patients with cumulative doses greater than or equal to 20.0g have almost 6 times more chance of infections (OR=5.89, 95% CI, 1.1–31.3) than those with smaller cumulative doses.DiscussionThe introduction of CF in the rheumatology armamentarium has led to an increase in survival of 10% per year in untreated patients to 80% in severe conditions such as WG.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Moreover, its use in patients with severe forms of SLE is associated both with an increase in survival and a decline in chronic renal failure in patients with renal compromise.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>The usually mild infectious processes are the most common complication of patients treated with CF. Martin et al. analyzed 451 boluses in 75 CF patients with different rheumatic diseases, finding 28% of infections, while only 9% of patients presented a serious infection.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>15% of our patients had a severe infection, the most common being community-acquired pneumonia. Other researchers have reported a lower rate of serious infections using a lower dose of CF.<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a> The second most common infection in our study was Herpes in 2 cases (22%), a percentage similar to reports by others.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Reversible myelosuppression is common with the use of CF, and the degree of leuco/neutropenia and thus the risk of infection is related to the dose used. Also, prolonged use leads to greater sensitivity for bone marrow suppression.<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> In our series, leuko/neutropenia was seen in one case and had no serious impact on the patient.Increased susceptibility to infections is also one of the most common side effects of steroid use. This complication is related to the time of use, the doses and cumulative doses.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Steroid use was the only statistically significant factor associated with infections in our patients.None of our patients died as a result of infection, possibly due to early and intensive antibiotic treatment.The main limitation of this study is its retrospective nature; however, it reflects daily clinical practice, where patients are very heterogeneous, as are the treatments instituted, as there were patients who had to be retreated with CF due to the severity of their affection and, in 2 cases, the need for oral therapy for a time.While infections are one of the most feared adverse events in patients using CF, in our series there was 15% of serious infections, which did not cause the death of any patient related to the dose of corticosteroids received.In conclusion, we believe that strict monitoring associated with the use of corticosteroids in the lowest possible dose and aggressive treatment of infectious processes allows for an acceptable safety profile in patients with severe autoimmune diseases who need to be treated with CF.Ethical ResponsibilitiesProtection of human and animal subjectsThe authors declare this research did not perform experiments on humans or animals.Confidentiality of dataThe authors declare that they have followed the protocols of their workplace regarding the publication of patient data.Right to privacy and informed consentThe authors have obtained the informed consent of patients and/or subjects referred to in the article. This document is in the possession of the corresponding author.Conflicts of InterestThe authors have no conflicts of interest to state." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres528597" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec548834" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres528596" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec548835" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical Analysis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of Interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-05-21" "fechaAceptado" => "2014-09-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec548834" "palabras" => array:5 [ 0 => "Connective tissue diseases" 1 => "Infections" 2 => "Immunosuppressive drugs" 3 => "Cyclophosphamide" 4 => "Corticosteroids" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec548835" "palabras" => array:5 [ 0 => "Enfermedades autoinmunes sistémicas" 1 => "Infecciones" 2 => "Inmunosupresores" 3 => "Ciclofosfamida" 4 => "Corticoides" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionInfectious diseases are a significant cause of morbidity and mortality in patients with connective tissue diseases. Corticosteroids and immunosuppressive drugs, such as cyclophosphamide (CYC), increase the risk of infections. The objective of this study was to estimate the incidence rates of severe infections in patients who received treatment with CYC. Patients and methodsThe records of 60 patients with systemic autoimmune diseases who received treatment with CYC were retrospectively reviewed. We evaluated the rate of severe infections that occurred during CYC therapy and the 3 subsequent months. ResultsSystemic lupus erythematosus was the most common disease, and diffuse proliferative glomerulonephritis the most frequent indication. Severe infection occurred in 9 patients (15%). Community acquired pneumonia was the most frequent infection with 3 cases (33%) followed by Herpes Zoster with 2 reports (22%). The cumulative dose of corticosteroid was the only significant risk factor for infection, 32.8±16.7 vs 20.1±15.3, P=0.007. ConclusionThe use of lower doses of corticosteroids and an aggressive management of infectious complications allow for an acceptable safety profile in patients treated with CYC." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónLas infecciones son una de las principales causas de morbimortalidad en los pacientes con enfermedades autoinmunes sistémicas. Los corticoides y los inmunosupresores como la ciclofosfamida (CF) son algunos de los factores que se asocian a esta complicación. El objetivo de este estudio fue determinar el porcentaje de pacientes que presentaron infecciones graves durante el tratamiento con CF y en los 3 meses posteriores. Pacientes y métodosSe realizó un análisis retrospectivo de 60 pacientes con diferentes enfermedades autoinmunes que recibieron tratamiento con CF. Se valoró el porcentaje de infecciones graves. ResultadosLa patología mñas común fue el lupus eritematoso sistémico y la indicación más común fue la glomerulonefritis proliferativa difusa. El 15% de los pacientes presentó un episodio infeccioso. Las infecciones más frecuentes fueron neumonía adquirida en la comunidad en 3 casos y herpes zóster en 2 casos. La dosis acumulada de corticoides fue el único parámetro que se asoció a infecciones 32,8±16,7 vs. 20,1±15,3 p=0,007. ConclusiónUn seguimiento estricto, la utilización de corticoides en la menor dosis posible y el tratamiento enérgico de los procesos infecciosos permiten un perfil de seguridad aceptable en aquellos pacientes tratados con CF." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Cavallasca JA, Costa CA, Maliandi MR, Contini LE, Fernandez de Carrera E, Musuruana JL. Infecciones severas en pacientes con enfermedades autoinmunes tratados con ciclofosfamida. Reumatol Clin. 2015;11:221–223." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Infections \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Community-acquired pneumonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Herpes zoster \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Soft tissue infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Catheter-related infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Pyelonephritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Febrile neutropenia with mucositis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab851787.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Documented Infections." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Significant P-value <.05.SD: standard deviation." "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"><th class="td" title="table-head " align="left" valign="top" scope="col">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Patients</th><th class="td" title="table-head " align="left" valign="top" scope="col">P value \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Overall(No.=60) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No infection(No.=51) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">With infection(No.=9) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Gender, female/male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48/12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40/11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8/1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.671<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age (years), mean±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42.8±14.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43.2±14.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40.5±12.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.534<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CF cumulative dose (g), mean±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14.3±25.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13.1±24.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20.6±31.01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.283<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cumulative doses of corticosteroids (g), mean±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22.04±16.07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20.1±15.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32.8±16.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.007<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab851788.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Fisher exact test." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Mann–Whitney." ] ] ] "descripcion" => array:1 [ "en" => "Comparison of Doses Received Between Patients With and Without Infection." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and polymyositis/dermatomyositis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. 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Severe Infections in Patients With Autoimmune Diseases Treated With Cyclophosphamide

Infecciones graves en pacientes con enfermedades autoinmunes tratados con ciclofosfamida

Javier A. Cavallasca

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jcavallasca@yahoo.com.ar

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, Cecilia A. Costa, Maria del Rosario Maliandi, Liliana E. Contini, Elena Fernandez de Carrera, Jorge L. Musuruana

Sección Reumatología y Enfermedades Autoinmunes Sistémicas, Hospital J.B. Iturraspe, Santa Fe, Argentina

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it also considered its relationship with the type of rheumatic disease and the cumulative dose of CF and corticosteroids&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">The medical records of 60 patients with <span class="elsevierStyleItalic">systemic autoimmune</span> diseases seen at the Rheumatology and Systemic Autoimmune Diseases Section of the Hospital Iturraspe JB in Santa Fe&#44; Argentina&#44; who were treated with CF between November 1996 and March 2011&#44; were retrospectively reviewed&#46; Demographics of each patient&#44; the reason for using CF&#44; concomitant steroid use&#44; cumulative dose of CF and corticosteroids&#44; infection&#44; need for hospitalization and&#47;or antibiotics&#47;antivirals were analyzed&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical Analysis</span><p id="par0030" class="elsevierStylePara elsevierViewall">An observational&#44; 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In this case there were 4 patients with cumulative doses higher than 54&#46;0<span class="elsevierStyleHsp" style=""></span>g&#44; one of which &#40;cumulative dose 69&#46;7<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#41;</span> presented infection&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">It should be noted that patients with cumulative doses of CF considered atypical are not the same as those that had high cumulative doses of corticosteroids&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">During follow-up&#44; 2 patients with severe forms of granulomatosis with polyangiitis &#40;Wegener&#39;s granulomatosis &#91;WG&#93;&#41; received oral CF for a time&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">15&#37; of patients &#40;n&#61;9&#41; had at least one infectious episode during treatment with CF&#46; The most frequent infections were community acquired pneumonia &#40;CAP&#41;&#44; 3 cases &#40;33&#37;&#41; and herpes zoster&#44; 2 cases &#40;22&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A single case presented leucopenia with neutropenia at time of infection&#46; None of the patients died as a result of the infectious process&#46; The time from the start of treatment with CF and infectious symptoms ranged between 2 and 66 months&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">When comparing the group of patients who were infected with those who were not&#44; no statistically significant differences regarding age &#40;<span class="elsevierStyleItalic">P&#61;</span>0&#46;534&#41;&#44; gender &#40;<span class="elsevierStyleItalic">P&#61;</span>0&#46;675&#41; and cumulative dose of CF were found at the time of infection &#40;<span class="elsevierStyleItalic">P&#61;</span>0&#46;283&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">When analyzing the cumulative dose of steroids and comparing them between patients with and without infection&#44; it was observed that all patients who developed infections had a cumulative dose between 15&#46;0 and 69&#46;6<span class="elsevierStyleHsp" style=""></span>g&#44; while those in which there was no infectious process&#44; the dose ranged between 3&#46;0 and 90&#46;6<span class="elsevierStyleHsp" style=""></span>g&#46; Furthermore&#44; in 50&#37; of patients without infection the accumulated dose was 16&#46;0<span class="elsevierStyleHsp" style=""></span>g or less&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Cumulative corticosteroid doses in patients with and without infection were compared&#44; finding significant differences &#40;<span class="elsevierStyleItalic">P</span>&#61;0&#46;007&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A cutoff was established in the cumulative steroid doses of 20&#46;0<span class="elsevierStyleHsp" style=""></span>g&#44; which coincided with the 75th percentile of the dose values of patients who were not infected &#46;A statistically significant association between high levels of cumulative dose of steroids and infection &#40;<span class="elsevierStyleItalic">P</span>&#61;0&#46;029&#41; was found&#44; which would indicate that patients with cumulative doses greater than or equal to 20&#46;0<span class="elsevierStyleHsp" style=""></span>g have almost 6 times more chance of infections &#40;OR&#61;5&#46;89&#44; 95&#37; CI&#44; 1&#46;1&#8211;31&#46;3&#41; than those with smaller cumulative doses&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">The introduction of CF in the rheumatology armamentarium has led to an increase in survival of 10&#37; per year in untreated patients to 80&#37; in severe conditions such as WG&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Moreover&#44; its use in patients with <span class="elsevierStyleItalic">severe</span> forms of SLE is associated both with an increase in survival and a decline in chronic renal failure in patients with renal compromise&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The usually mild infectious processes are the most common complication of patients treated with CF&#46; Martin et al&#46; analyzed 451 boluses in 75 CF patients with different rheumatic diseases&#44; finding 28&#37; of infections&#44; while only 9&#37; of patients presented a <span class="elsevierStyleItalic">serious</span> infection&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">15&#37; of our patients had a <span class="elsevierStyleItalic">severe</span> infection&#44; the most common being community-acquired pneumonia&#46; Other researchers have reported a lower rate of serious infections using a lower dose of CF&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> The second most common infection in our study was Herpes in 2 cases &#40;22&#37;&#41;&#44; a percentage similar to reports by others&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Reversible myelosuppression is common with the use of CF&#44; and the degree of leuco&#47;neutropenia and thus the risk of infection is related to the dose used&#46; Also&#44; prolonged use leads to greater sensitivity for bone marrow suppression&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> In our series&#44; leuko&#47;neutropenia was seen in one case and had no serious impact on the patient&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Increased susceptibility to infections is also one of the most common side effects of steroid use&#46; This complication is related to the time of use&#44; the doses and cumulative doses&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Steroid use was the only statistically significant factor associated with infections in our patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">None of our patients died as a result of infection&#44; possibly due to early and intensive antibiotic treatment&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The main limitation of this study is its retrospective nature&#59; however&#44; it reflects daily clinical practice&#44; where patients are very heterogeneous&#44; as are the treatments instituted&#44; as there were patients who had to be retreated with CF due to the severity of their affection and&#44; in 2 cases&#44; the need for oral therapy for a time&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">While infections are one of the most feared adverse events in patients using CF&#44; in our series there was 15&#37; of serious infections&#44; which did not cause the death of any patient related to the dose of corticosteroids received&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In conclusion&#44; we believe that strict monitoring associated with the use of corticosteroids in the lowest possible dose and aggressive treatment of infectious processes allows for an acceptable safety profile in patients with severe autoimmune diseases who need to be treated with CF&#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 human and animal subjects</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare this research did not perform experiments on humans or animals&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Confidentiality of data</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their workplace regarding the publication of patient data&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Right to privacy and informed consent</span><p id="par0150" 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">Conflicts of Interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to state&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "identificador" => "xres528597"
          "titulo" => "Abstract"
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            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Introduction"
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            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Patients and methods"
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              "identificador" => "abst0015"
              "titulo" => "Results"
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              "titulo" => "Conclusion"
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          "identificador" => "xpalclavsec548834"
          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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            0 => array:2 [
              "identificador" => "abst0025"
              "titulo" => "Introducci&#243;n"
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            1 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Pacientes y m&#233;todos"
            ]
            2 => array:2 [
              "identificador" => "abst0035"
              "titulo" => "Resultados"
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            3 => array:2 [
              "identificador" => "abst0040"
              "titulo" => "Conclusi&#243;n"
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          "identificador" => "xpalclavsec548835"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Materials and Methods"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Statistical Analysis"
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        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Results"
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          "identificador" => "sec0025"
          "titulo" => "Discussion"
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          "identificador" => "sec0030"
          "titulo" => "Ethical Responsibilities"
          "secciones" => array:3 [
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              "identificador" => "sec0035"
              "titulo" => "Protection of human and animal subjects"
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            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Confidentiality of data"
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            2 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Right to privacy and informed consent"
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          "identificador" => "sec0050"
          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2014-05-21"
    "fechaAceptado" => "2014-09-19"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec548834"
          "palabras" => array:5 [
            0 => "Connective tissue diseases"
            1 => "Infections"
            2 => "Immunosuppressive drugs"
            3 => "Cyclophosphamide"
            4 => "Corticosteroids"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec548835"
          "palabras" => array:5 [
            0 => "Enfermedades autoinmunes sist&#233;micas"
            1 => "Infecciones"
            2 => "Inmunosupresores"
            3 => "Ciclofosfamida"
            4 => "Corticoides"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Infectious diseases are a significant cause of morbidity and mortality in patients with connective tissue diseases&#46; Corticosteroids and immunosuppressive drugs&#44; such as cyclophosphamide &#40;CYC&#41;&#44; increase the risk of infections&#46; The objective of this study was to estimate the incidence rates of severe infections in patients who received treatment with CYC&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The records of 60 patients with systemic autoimmune diseases who received treatment with CYC were retrospectively reviewed&#46; We evaluated the rate of severe infections that occurred during CYC therapy and the 3 subsequent months&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Systemic lupus erythematosus was the most common disease&#44; and diffuse proliferative glomerulonephritis the most frequent indication&#46; Severe infection occurred in 9 patients &#40;15&#37;&#41;&#46; Community acquired pneumonia was the most frequent infection with 3 cases &#40;33&#37;&#41; followed by Herpes Zoster with 2 reports &#40;22&#37;&#41;&#46; The cumulative dose of corticosteroid was the only significant risk factor for infection&#44; 32&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;7 vs 20&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;3&#44; <span class="elsevierStyleItalic">P</span>&#61;0&#46;007&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The use of lower doses of corticosteroids and an aggressive management of infectious complications allow for an acceptable safety profile in patients treated with CYC&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Patients and methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las infecciones son una de las principales causas de morbimortalidad en los pacientes con enfermedades autoinmunes sist&#233;micas&#46; Los corticoides y los inmunosupresores como la ciclofosfamida &#40;CF&#41; son algunos de los factores que se asocian a esta complicaci&#243;n&#46; El objetivo de este estudio fue determinar el porcentaje de pacientes que presentaron infecciones graves durante el tratamiento con CF y en los 3 meses posteriores&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un an&#225;lisis retrospectivo de 60 pacientes con diferentes enfermedades autoinmunes que recibieron tratamiento con CF&#46; Se valor&#243; el porcentaje de infecciones graves&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La patolog&#237;a m&#241;as com&#250;n fue el lupus eritematoso sist&#233;mico y la indicaci&#243;n m&#225;s com&#250;n fue la glomerulonefritis proliferativa difusa&#46; El 15&#37; de los pacientes present&#243; un episodio infeccioso&#46; Las infecciones m&#225;s frecuentes fueron neumon&#237;a adquirida en la comunidad en 3 casos y herpes z&#243;ster en 2 casos&#46; La dosis acumulada de corticoides fue el &#250;nico par&#225;metro que se asoci&#243; a infecciones 32&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#44;7 vs&#46; 20&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#44;3 p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;007&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Un seguimiento estricto&#44; la utilizaci&#243;n de corticoides en la menor dosis posible y el tratamiento en&#233;rgico de los procesos infecciosos permiten un perfil de seguridad aceptable en aquellos pacientes tratados con CF&#46;</p></span>"
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            "titulo" => "Pacientes y m&#233;todos"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Cavallasca JA&#44; Costa CA&#44; Maliandi MR&#44; Contini LE&#44; Fernandez de Carrera E&#44; Musuruana JL&#46; Infecciones severas en pacientes con enfermedades autoinmunes tratados con ciclofosfamida&#46; Reumatol Clin&#46; 2015&#59;11&#58;221&#8211;223&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Community-acquired pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Herpes zoster&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Soft tissue infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Catheter-related infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Pyelonephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Febrile neutropenia with mucositis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Documented Infections&#46;</p>"
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Significant <span class="elsevierStyleItalic">P</span>-value &#60;&#46;05&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">SD&#58; standard deviation&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Patients</th><th class="td" title="table-head  " align="left" valign="top" scope="col"><span class="elsevierStyleItalic">P</span> value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Overall&#40;No&#46;&#61;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No infection&#40;No&#46;&#61;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">With infection&#40;No&#46;&#61;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Gender&#44; female&#47;male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48&#47;12&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2014.11.002

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2024 March	46	28	74
2024 February	30	23	53
2024 January	31	30	61
2023 December	47	25	72
2023 November	59	33	92
2023 October	62	38	100
2023 September	63	35	98
2023 August	35	10	45
2023 July	56	30	86
2023 June	47	21	68
2023 May	71	29	100
2023 April	47	8	55
2023 March	74	33	107
2023 February	58	25	83
2023 January	58	34	92
2022 December	65	40	105
2022 November	51	32	83
2022 October	72	29	101
2022 September	39	40	79
2022 August	51	44	95
2022 July	40	50	90
2022 June	38	38	76
2022 May	46	42	88
2022 April	64	71	135
2022 March	67	51	118
2022 February	62	32	94
2022 January	59	43	102
2021 December	42	30	72
2021 November	48	44	92
2021 October	98	84	182
2021 September	57	36	93
2021 August	72	57	129
2021 July	69	41	110
2021 June	63	42	105
2021 May	79	31	110
2021 April	197	114	311
2021 March	141	32	173
2021 February	110	23	133
2021 January	108	26	134
2020 December	96	26	122
2020 November	104	31	135
2020 October	101	20	121
2020 September	67	29	96
2020 August	63	18	81
2020 July	58	12	70
2020 June	61	28	89
2020 May	74	19	93
2020 April	39	15	54
2020 March	23	6	29
2020 February	1	0	1
2018 May	7	1	8
2018 April	50	3	53
2018 March	48	8	56
2018 February	25	2	27
2018 January	20	6	26
2017 December	36	10	46
2017 November	25	7	32
2017 October	36	9	45
2017 September	28	18	46
2017 August	28	9	37
2017 July	43	12	55
2017 June	58	8	66
2017 May	47	20	67
2017 April	34	5	39
2017 March	25	12	37
2017 February	12	6	18
2017 January	21	8	29
2016 December	58	15	73
2016 November	40	10	50
2016 October	68	13	81
2016 September	59	14	73
2016 August	46	8	54
2016 July	26	14	40
2015 December	3	0	3
2015 November	1	19	20
2015 October	3	21	24
2015 September	3	0	3
2015 August	5	37	42
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