Rituximab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis

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Fernández, Ciudad Autónoma de Buenos Aires, Argentina" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital Aeronáutico Central, Ciudad Autónoma de Buenos Aires, Argentina" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Exjefe del Servicio de Clínica Médica División «A», Hospital General de Agudos Juan A. Fernández, Ciudad Autónoma de Buenos Aires, Argentina" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Rituximab en el tratamiento de la granulomatosis eosinofílica con poliangitis" ] ] "textoCompleto" => "IntroductionEGPA is a necrotizing vasculitis that primarily affects small and medium caliber blood vessels, and is defined as a granulomatous inflammatory and necrotizing disease rich in eosinophils that often affects the airway and is characterized by the presence of asthma and eosinophilia. Along with granulomatosis with polyangiitis (Wegener's granulomatosis [GPA]) and microscopic polyangiitis (MPA), they are part of the antineutrophil cytoplasm antibodies (ANCA) associated vasculitis (AAV).<a class="elsevierStyleCrossRef" href="#bib0150">1</a>The general consensus is to treat severe forms of EGPA, defined as those with a score on the 5 factor score (FFS) equal to or greater than 1, with glucocorticoids (GC) and cyclophosphamide (CYP) to achieve clinical remission. Maintaining remission is achieved using GC and AZA. Mild forms (FFA of 0) are treated with GC alone. However, the high rate of adverse events, lack of response to induction treatment or frequent relapses with first line treatments require the study of therapeutic alternatives.<a class="elsevierStyleCrossRefs" href="#bib0155">2–4</a>Rituximab (RTX) is a chimeric monoclonal antibody that specifically binds the CD20 antigen, a non-glycosilated transmembrane phosphoprotein expressed on pre-B and B lymphocytes. The reasonable use of this drug in EGPA is mainly based on its good results in case reports and small series of patients who have been refractory to first line treatment and, in addition is supported by its proven efficacy in clinical trials for AAV patients (GPA and MPA).<a class="elsevierStyleCrossRefs" href="#bib0170">5–8</a> As patients with EGPA were not included in these trials, RTX approval was not extended to EGPA.The purpose of this study is to review and analyze the studies published in the literature on the use of RTX in the treatment of EGPA.Materials and MethodsLiterature search strategy: we consulted the databases of the Medical Literature Analysis and Retrieval System on Line (MEDLINE)/National Library of Medicine (NLM)-Library of Medicine of the United States and the Latin American and Caribbean Literature in Health Sciences (LILACS) library, since 1965 and 1986 respectively, until February 2014. Search terms in English and Spanish were Churg-Strauss (síndrome de Churg-Strauss) syndrome, eosinophilic granulomatosis with polyangiitis (granulomatosis eosinofílica conpoliangitis), allergic granulomatous angiitis (angeí-tis granulomatosa alérgica), RXT and monoclonal anti-CD20 (anti-CD20 monoclonal antibody).The following data were analyzed: age, sex, affected organs/systems when RTX was indicated, clinical disease state (defined as relapse, treatment resistant or new diagnosis), ANCA determination, eosinophil and B lymphocyte counts in peripheral blood, number of immunosuppressive used before and after treatment with RTX, clinical patient progression and adverse events.We excluded all those publications that did not have detailed data from the final analysis.Statistical analysis: Qualitative variables were presented as percentages, and quantitative variables as means±standard deviations or median with minimal and maximum values.Results<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the general characteristics of 27 patients with a diagnosis of EGPA included for analysis. Fifteen (55.5%) were male and 12 (44.5%) were female. Median follow-up was 15 months (3–60 months). The indication for RTX treatment was refractory disease in 20 (74.1%), relapse in 5 (18.5%) and a new diagnosis in 2 (7.4%) patients.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The affected organs that prompted the use of RTX were the lungs (n=18, 66.6%) (asthma, pulmonary infiltrates or alveolar hemorrhage), the peripheral nervous system (n=16, 59.3%) (mono- or polyneuropathy), kidneys (n=9, 33.3%), eyes (n=9, 33.3%) and heart (n=6, 22.2%) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).ANCA were reported in 14 patients (51.8%), 11 (78.6%) with a perinuclear pattern (P-ANCA) and 3 (21.4%) with a cytoplasmic pattern (C-ANCA). In 10 (33.1%) patients, ANCA were negative and in 3 (11.1%) the ANCA status was not reported. The number of eosinophils, before the start of treatment with RTX, was elevated in all patients (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The median of immunosuppressive drugs (including GC) used before the start of treatment with RTX was 3 (range 1–6).The treatment strategies with RTX employed were: 375mg/m2 of total body surface every 7 days, a total of 4 infusions (n=8; 2) 1000mg every 15 days, a total of 2 infusions (n=13) and variants of these (n=4).In 2 patients the RTX infusion was suspended due to adverse reactions, making it unable to finish the therapy.Excluding the use of GC, 14 patients used another immunosuppressive drug concomitantly with RTX (CYP, AZA, methotrexate and mycophenolate mofetil).Response to TreatmentClinical disease remission was seen in 16 (59.2%) patients and response in 8 (29.6%) patients (<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>In 3 (12%) patients a relapse was observed and in 2 of them this coincided with the reappearance of CD20+B lymphocytes in peripheral blood. All 3 patients were retreated with RTX, with a clinical response.<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the evolution of ANCA, eosinophil counts and the determination of CD20+B lymphocytes in patients before and after the administration of RTX.Adverse events reported are detailed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. In 2 patients the first infusion of RTX had to be suspended due to serious bronchospasm; the remaining adverse events were respiratory infections and an episode of herpes zoster. One patient was diagnosed with a seminoma 12 months after receiving RTX. There were no deaths.DiscussionEGPA belongs to the group of AAV along with GPA and MPA; however, it differs from them in several ways. The current treatment of EGPA is similar to that of the remaining AAV, but differs in that RTX has no defined indication as in GPA and MPA, as the randomized clinical trials such as the RAVE and RITUXVAS<a class="elsevierStyleCrossRefs" href="#bib0170">5,6</a> did not include patients with EGPA. So far, there are only anecdotal reports of EGPA patients treated with RTX, which makes it difficult to assess the effectiveness of this drug in this disease.An analysis of the literature shows that most EGPA patients treated with RTX were refractory to first line treatment or relapsed during maintenance immunosuppressive therapy. Only 5 patients received RTX as first line induction treatment (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).In all patients there was a rapid response observed after treatment with RTX; 2 patients did not complete the infusion of the drug due to a severe adverse reaction.<a class="elsevierStyleCrossRef" href="#bib0205">12</a> Clinical disease remission was seen in most patients. Three patients had one or more relapses, but responded to a new cycle of RTX. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the response to treatment with RTX of cases analyzed along with 2 sets of cases recently reported as abstracts.<a class="elsevierStyleCrossRefs" href="#bib0255">22,23</a>A major problem in patients with EGPA is the persistence of symptoms of asthma, despite treatment and the morbidity dependent on long-term GC treatment. While the studies did not analyze the therapeutic response of asthma to RTX, a recent communication presented at the 16th International Vasculitis & ANCA Workshop (Paris, France) by Hot et al. found that 39% of patients treated with RTX for EGPA continued with GC requirements due to persistent asthma.<a class="elsevierStyleCrossRef" href="#bib0260">23</a>Decreased values of peripheral blood eosinophil were reduced or normal after treatment with RTX regardless of the dosage regimen used, in most patients. This finding puts the close relationship that the different cells of the immune system, and especially the strong Th2 lymphocyte interaction through the secretion of cytokines (IL-4, IL-5 and IL-13), with the B cell and the subsequent production and secretion of eotaxin-1, IgG4, IgE and ANCA in perspective.<a class="elsevierStyleCrossRefs" href="#bib0155">2,24</a> IgE is elevated in the serum of patients with EGPA. This immunoglobulin, which is produced by plasma cells, is bound to receptors (Fc¿R1) on the surface of eosinophils, which, by binding to antigen, induces their involvement in the inflammatory response. Furthermore, eotaxin-1 participates in the recruitment of eosinophils to the site of inflamation.<a class="elsevierStyleCrossRef" href="#bib0155">2</a> These mechanisms could explain in part the decline of eosinophils after treatment with RTX.Circulating CD20+lymphocytes after RTX use were undetectable and thus persisted for variable time. The period until the repopulation of CD20+B cells was not uniform and in some patients was not correlated with the clinical evolution of the disease. In the RAVE<a class="elsevierStyleCrossRef" href="#bib0175">6</a> study, a high percentage of patients had undetectable CD20+B cell counts after the infusion of RTX (as occurred in the group using CYP) and the time to repopulation thereof was variable. Of greater importance was the finding regarding the repopulation of CD20+B lymphocytes as an isolated variable that did not predict the relapse risk in the individual patient. However, patients who after the use of RTX persisted with undetectable CD20+B lymphocyte levels and negative ANCA were unlikely to relapse.ANCA are not the only pathogenic mechanism involved in the genesis of this vasculitis; EGPA patients have a strong IgG4 response regardless of the status of ANCA; evidence of a dialog between the B lymphocytes and eosinophils, and the ability of the B cell to secrete eotaxin-1, which is involved in the recruitment of eosinophils at sites of inflammation<a class="elsevierStyleCrossRefs" href="#bib0265">24–26</a> could be another pathogenic mechanism involved in the response mediated by RTX; therefore the fact that a patient is ANCA negative does not predict a failure to respond to treatment with RTX.RTX was well tolerated; only 2 patients experienced adverse reactions during infusion. Adverse events were minor, usually respiratory infections in outpatient care. No deaths directly attributed to RTX were reported. This is consistent with the adverse effects reported in large series and extensive clinical studies demonstrating the safety of RTX in the treatment of AAV.<a class="elsevierStyleCrossRefs" href="#bib0170">5–8</a>The most commonly used treatment strategies were: RTX 1000mg every 15 days (total 2 infusions) and 375mg/m2 of RTX per week (total of 4 infusions). Although both strategies were not formally compared, they appear to be equally effective for the induction of remission in the AAV; the expert recommendation on the use of RTX in AAV is to use both strategies interchangeably.<a class="elsevierStyleCrossRef" href="#bib0280">27</a>This study has limitations: the number of patients is small, follow-up time is limited, definitions of activity and damage were not uniform – only in some studies was the Birmingham Vasculitis Activity Score used, and in different versions, immunosuppressive drugs and use of RTX differed between patients. In addition, we did not find publications regarding EGPA patients who did not respond to RTX.However, there is a widespread tendency to reconsider the standards of treatment for AAV, including EGPA, both in the induction as well as in the maintenance.<a class="elsevierStyleCrossRefs" href="#bib0285">28,29</a>Finally, RTX appears to be effective and safe for the treatment of refractory EGPA, relapses or newly diagnosed, independent ANCA status. Randomized clinical trials are necessary to confirm this observation.Ethical ResponsibilitiesProtection of people and animalsThe authors declare that this research did not perform experiments on humans or animals.Data privacyThe authors state that no patient data appear in this article.Right to privacy and informed consentThe authors state that no patient data appear in this article.Conflict of InterestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres493498" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec515320" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres493499" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec515321" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and Methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Response to Treatment" ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 8 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of people and animals" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Data privacy" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-03-11" "fechaAceptado" => "2014-08-08" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec515320" "palabras" => array:3 [ 0 => "Rituximab" 1 => "Eosinophilic granulomatosis with polyangiitis" 2 => "Antineutrophil cytoplasmic antibodies associated vasculitis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec515321" "palabras" => array:3 [ 0 => "Rituximab" 1 => "Granulomatosis eosinofílica con poliangitis" 2 => "Vasculitis asociadas a anticuerpos anticitoplasma de neutrófilo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe general consensus is that for patients with EGPA with poor prognosis, intensive therapy with both GC and CF is indicated. The maintenance of remission is made with GC and AZA. A considerable number of patients with EGPA are refractory to first line therapy, experience dose-limiting side effects or relapse. In clinical trials, RTX was effective for the treatment of ANCA-associated vasculitis. However, patients with a diagnosis of EGPA were not included. ObjectiveTo review and analyze the published literature regarding the use of RTX in the treatment of EGPA. MethodsThe literature search was performed in MEDLINE and LILACS from 1965 and 1986 respectively until February 2014. Results27 patients were included. RTX treatment was due to refractory disease (n=20), relapse (n=5) and with new diagnosis (n=2). The affected organs were the lungs, peripheral nervous system, kidney and the eyes. Sixteen patients had clinical remission and 8 patients had clinical response. ConclusionsRTX was effective and well tolerated for the treatment of EGPA." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesAlgunos pacientes con granulomatosis eosinofílica con poliangitis (EGPA) y factores de mal pronóstico son refractarios o presentan efectos adversos al tratamiento de inducción (glucocorticoides [GC] y ciclofosfamida [CF]), o recaen durante el mantenimiento (GC y azatioprina), haciendo necesaria la búsqueda de alternativas terapéuticas. En ensayos clínicos, el RTX demostró ser eficaz para el tratamiento de las vasculitis asociadas al ANCA; sin embargo, los pacientes con EGPA no fueron incluidos. ObjetivoRevisar y analizar la bibliografía sobre la uso de RTX para el tratamiento de la EGPA. MétodosLa búsqueda se realizó en MEDLINE y LILACS (1965 y 1986, respectivamente, hasta febrero del 2014). ResultadosSe incluyó a 27 pacientes. La indicación de RTX fue por enfermedad refractaria (n=20), recaída (n=5) y nuevo diagnóstico (n=2). Los órganos afectados fueron los pulmones, el sistema nervioso periférico, el riñón y los ojos. Se observó remisión en 16 y respuesta en 8 pacientes. ConclusionesEl RTX fue eficaz y bien tolerado para el tratamiento de la EGPA." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Muñoz SA, Gandino IJ, Orden AO, Allievi A. Rituximab en el tratamiento de la granulomatosis eosinofílica con poliangitis. Reumatol Clin. 2015;11:165–169." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "AZA: azathioprine; CF: cyclophosphamide; CSP: cyclosporin; ND: new diagnosis; F: female; Ig: immunoglobulin; M: male; MFM: mycohenolate mofetil; MP: methylprednisolone; MTX: methotrexate, NA: not applicable; NR: not reported; PF: plasmapheresis; PS: prednisone; Rl: relapse; Rf: refractory; RP: response; RM: remission; CNS: central nervous system; PNS: peripheral nervous system; RTX: rituximab; UA: upper airway." "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">Patient/reference \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">Age/gender \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">Status \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">Organs affected \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">Previous and concomitant treatments \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">Time of follow up(Months) \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. of cyclesof RTX and indication \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">Result \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">Adverse events \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">1<a class="elsevierStyleCrossRef" href="#bib0190">9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin, lung \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pneumonia, herpes zoster \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">2<a class="elsevierStyleCrossRef" href="#bib0195">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, PNS, VAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, Ig, MFM, Alemtuzumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (relapse) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">3<a class="elsevierStyleCrossRef" href="#bib0195">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, VAS, PNS, articular \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA, MFM, INF Alemtuzumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Respiratory infection \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">4<a class="elsevierStyleCrossRef" href="#bib0200">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin, kidney, eye \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MP, PS, CF, PF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">5<a class="elsevierStyleCrossRef" href="#bib0200">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, heart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MP, PS, Ig, CF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">6<a class="elsevierStyleCrossRef" href="#bib0205">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, joints, skin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MP, PS, CF, Ig \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">7<a class="elsevierStyleCrossRef" href="#bib0210">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, lung \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, AZA, MTX, CF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bronchospasm \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">8<a class="elsevierStyleCrossRef" href="#bib0210">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Joint \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, MFM, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bronchospasm \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">9<a class="elsevierStyleCrossRef" href="#bib0215">14</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">46/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, MFM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">10<a class="elsevierStyleCrossRef" href="#bib0220">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, ear \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, AZA, MTX, CSP, infliximab, anakinra \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (prophylaxis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">11<a class="elsevierStyleCrossRef" href="#bib0220">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung VAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (prophylaxis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">12<a class="elsevierStyleCrossRef" href="#bib0225">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, joint \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (relapse) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">13<a class="elsevierStyleCrossRef" href="#bib0230">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (relapse) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">14<a class="elsevierStyleCrossRef" href="#bib0230">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, kidney, lung \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">15<a class="elsevierStyleCrossRef" href="#bib0230">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">64/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, kidney, muscle \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">16<a class="elsevierStyleCrossRef" href="#bib0235">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">59/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">17<a class="elsevierStyleCrossRef" href="#bib0240">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS, febrile syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MP, PS, Ig, CF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">18<a class="elsevierStyleCrossRef" href="#bib0245">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MP, CF, PF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">19<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, heart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \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><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">20<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, heart, PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \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><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">21<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, PNS, SNC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, MTX, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \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><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">22<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, heart, CNS, skin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (prophylaxis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">23<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, heart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (prophylaxis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Seminoma \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">24<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, PNS, skin, kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, MFM, MTX, LF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (prophylaxis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">25<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, heart, skin, PNS, CNS, kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, AZA, CF, MTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \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><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">26<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rf \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, PNS, kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, CF, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \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><td class="td" title="table-entry " align="left" valign="top">RP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \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">27<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rc \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lung, eye, ear, PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PS, MTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \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><td class="td" title="table-entry " align="left" valign="top">RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab784591.png" ] ] ] ] "descripcion" => array:1 [ "en" => "General Characteristics of the 27 EGPA Patients Treated With RTX Until February 2014." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "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="" 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">Patients studied/total prior rituximab \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">Patients studied/total after rituximab \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">ANCA/specificity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24/27C (+): 12%P (+): 46%C and P (−): 42% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/27C (+): 0%P (+): 10%C and P (−): 90% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Eosinophil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22/27High: 100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22/27Descent: 55%Normal: 45% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD20+lymphocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16/27Normal: 100% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19/27Undetectable: 100% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab784589.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Details of the Presence of ANCA, Eosinophils and Lymphocytes CD20+ Before and After Treatment With RTX." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "NR: not reported." "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="" 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">No. patients (M/F) \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">Age(years) \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">Meanfollow up(months) \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">Indicationdisease(No.) \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">Responsen (%) \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">Cases analyzed<a class="elsevierStyleCrossRefs" href="#bib0190">9–21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27 (15/12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory (20)Relapse (5)New diag. (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Remission: 16 (59)Responded: 8 (29) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Dubrau et al.<a class="elsevierStyleCrossRef" href="#bib0255">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 (NR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory (5)Relapse (3)New diag. (3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Remission: 1 (9)Responded: 7 (64)No response 1 (9)Lost: 2 (18) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hot et al.<a class="elsevierStyleCrossRef" href="#bib0260">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 (16/14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Refractory or relapsed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Remission: 26 (88)Responded: 2 (6)No response: 2 (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab784590.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Details of Response to Treatment With RTX in EGPA Cases Analyzed and 2 Recent Series Reported in Abstracts." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.C. 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Rituximab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis

Rituximab en el tratamiento de la granulomatosis eosinofílica con poliangitis

Sebastián Andrés Muñoza,

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sebastianamunoz@gmail.com
aoorden@yahoo.com.ar

Corresponding author.

, Ignacio Javier Gandinoa, Alberto Omar Ordenb, Alberto Allievic

a Servicio de Clínica Médica División «A», Hospital General de Agudos Juan A. Fernández, Ciudad Autónoma de Buenos Aires, Argentina

b Servicio de Reumatología, Hospital Aeronáutico Central, Ciudad Autónoma de Buenos Aires, Argentina

c Exjefe del Servicio de Clínica Médica División «A», Hospital General de Agudos Juan A. Fernández, Ciudad Autónoma de Buenos Aires, Argentina

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">EGPA is a necrotizing vasculitis that primarily affects small and medium caliber blood vessels&#44; and is defined as a granulomatous inflammatory and necrotizing disease rich in eosinophils that often affects the airway and is characterized by the presence of asthma and eosinophilia&#46; Along with granulomatosis with polyangiitis &#40;Wegener&#39;s granulomatosis &#91;GPA&#93;&#41; and microscopic polyangiitis &#40;MPA&#41;&#44; they are part of the antineutrophil cytoplasm antibodies &#40;ANCA&#41; associated vasculitis &#40;AAV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The general consensus is to treat severe forms of EGPA&#44; defined as those with a score on the 5 factor score &#40;FFS&#41; equal to or greater than 1&#44; with glucocorticoids &#40;GC&#41; and cyclophosphamide &#40;CYP&#41; to achieve clinical remission&#46; Maintaining remission is achieved using GC and AZA&#46; Mild forms &#40;FFA of 0&#41; are treated with GC alone&#46; However&#44; the high rate of adverse events&#44; lack of response to induction treatment or frequent relapses with first line treatments require the study of therapeutic alternatives&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Rituximab &#40;RTX&#41; is a chimeric monoclonal antibody that specifically binds the CD20 antigen&#44; a non-glycosilated transmembrane phosphoprotein expressed on pre-B and B lymphocytes&#46; The reasonable use of this drug in EGPA is mainly based on its good results in case reports and small series of patients who have been refractory to first line treatment and&#44; in addition is supported by its proven efficacy in clinical trials for AAV patients &#40;GPA and MPA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">5&#8211;8</span></a> As patients with EGPA were not included in these trials&#44; RTX approval was not extended to EGPA&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The purpose of this study is to review and analyze the studies published in the literature on the use of RTX in the treatment of EGPA&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Literature search strategy</span>&#58; we consulted the databases of the Medical Literature Analysis and Retrieval System on Line &#40;MEDLINE&#41;&#47;National Library of Medicine &#40;NLM&#41;-Library of Medicine of the United States and the Latin American and Caribbean Literature in Health Sciences &#40;LILACS&#41; library&#44; since 1965 and 1986 respectively&#44; until February 2014&#46; Search terms in English and Spanish were Churg-Strauss &#40;s&#237;ndrome de Churg-Strauss&#41; syndrome&#44; eosinophilic granulomatosis with polyangiitis &#40;granulomatosis eosinof&#237;lica conpoliangitis&#41;&#44; allergic granulomatous angiitis &#40;ange&#237;-tis granulomatosa al&#233;rgica&#41;&#44; RXT and monoclonal anti-CD20 &#40;anti-CD20 monoclonal antibody&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The following data were analyzed&#58; age&#44; sex&#44; affected organs&#47;systems when RTX was indicated&#44; clinical disease state &#40;defined as relapse&#44; treatment resistant or new diagnosis&#41;&#44; ANCA determination&#44; eosinophil and B lymphocyte counts in peripheral blood&#44; number of immunosuppressive used before and after treatment with RTX&#44; clinical patient progression and adverse events&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We excluded all those publications that did not have detailed data from the final analysis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Statistical analysis</span>&#58; Qualitative variables were presented as percentages&#44; and quantitative variables as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviations or median with minimal and maximum values&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the general characteristics of 27 patients with a diagnosis of EGPA included for analysis&#46; Fifteen &#40;55&#46;5&#37;&#41; were male and 12 &#40;44&#46;5&#37;&#41; were female&#46; Median follow-up was 15 months &#40;3&#8211;60 months&#41;&#46; The indication for RTX treatment was refractory disease in 20 &#40;74&#46;1&#37;&#41;&#44; relapse in 5 &#40;18&#46;5&#37;&#41; and a new diagnosis in 2 &#40;7&#46;4&#37;&#41; patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The affected organs that prompted the use of RTX were the lungs &#40;n&#61;18&#44; 66&#46;6&#37;&#41; &#40;asthma&#44; pulmonary infiltrates or alveolar hemorrhage&#41;&#44; the peripheral nervous system &#40;n&#61;16&#44; 59&#46;3&#37;&#41; &#40;mono- or polyneuropathy&#41;&#44; kidneys &#40;n&#61;9&#44; 33&#46;3&#37;&#41;&#44; eyes &#40;n&#61;9&#44; 33&#46;3&#37;&#41; and heart &#40;n&#61;6&#44; 22&#46;2&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">ANCA were reported in 14 patients &#40;51&#46;8&#37;&#41;&#44; 11 &#40;78&#46;6&#37;&#41; with a perinuclear pattern &#40;P-ANCA&#41; and 3 &#40;21&#46;4&#37;&#41; with a cytoplasmic pattern &#40;C-ANCA&#41;&#46; In 10 &#40;33&#46;1&#37;&#41; patients&#44; ANCA were negative and in 3 &#40;11&#46;1&#37;&#41; the ANCA status was not reported&#46; The number of eosinophils&#44; before the start of treatment with RTX&#44; was elevated in all patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The median of immunosuppressive drugs &#40;including GC&#41; used before the start of treatment with RTX was 3 &#40;range 1&#8211;6&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The treatment strategies with RTX employed were&#58; 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> of total body surface every 7 days&#44; a total of 4 infusions &#40;n&#61;8&#59; 2&#41; 1000<span class="elsevierStyleHsp" style=""></span>mg every 15 days&#44; a total of 2 infusions &#40;n&#61;13&#41; and variants of these &#40;n&#61;4&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In 2 patients the RTX infusion was suspended due to adverse reactions&#44; making it unable to finish the therapy&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Excluding the use of GC&#44; 14 patients used another immunosuppressive drug concomitantly with RTX &#40;CYP&#44; AZA&#44; methotrexate and mycophenolate mofetil&#41;&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Response to Treatment</span><p id="par0080" class="elsevierStylePara elsevierViewall">Clinical disease remission was seen in 16 &#40;59&#46;2&#37;&#41; patients and response in 8 &#40;29&#46;6&#37;&#41; patients &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">In 3 &#40;12&#37;&#41; patients a relapse was observed and in 2 of them this coincided with the reappearance of CD20&#43;B lymphocytes in peripheral blood&#46; All 3 patients were retreated with RTX&#44; with a clinical response&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the evolution of ANCA&#44; eosinophil counts and the determination of CD20&#43;B lymphocytes in patients before and after the administration of RTX&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Adverse events reported are detailed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; In 2 patients the first infusion of RTX had to be suspended due to serious bronchospasm&#59; the remaining adverse events were respiratory infections and an episode of herpes zoster&#46; One patient was diagnosed with a seminoma 12 months after receiving RTX&#46; There were no deaths&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">EGPA belongs to the group of AAV along with GPA and MPA&#59; however&#44; it differs from them in several ways&#46; The current treatment of EGPA is similar to that of the remaining AAV&#44; but differs in that RTX has no defined indication as in GPA and MPA&#44; as the randomized clinical trials such as the RAVE and RITUXVAS<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">5&#44;6</span></a> did not include patients with EGPA&#46; So far&#44; there are only anecdotal reports of EGPA patients treated with RTX&#44; which makes it difficult to assess the effectiveness of this drug in this disease&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">An analysis of the literature shows that most EGPA patients treated with RTX were refractory to first line treatment or relapsed during maintenance immunosuppressive therapy&#46; Only 5 patients received RTX as first line induction treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In all patients there was a rapid response observed after treatment with RTX&#59; 2 patients did not complete the infusion of the drug due to a severe adverse reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> Clinical disease remission was seen in most patients&#46; Three patients had one or more relapses&#44; but responded to a new cycle of RTX&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the response to treatment with RTX of cases analyzed along with 2 sets of cases recently reported as abstracts&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">A major problem in patients with EGPA is the persistence of symptoms of asthma&#44; despite treatment and the morbidity dependent on long-term GC treatment&#46; While the studies did not analyze the therapeutic response of asthma to RTX&#44; a recent communication presented at the 16th International Vasculitis &#38; ANCA Workshop &#40;Paris&#44; France&#41; by Hot et al&#46; found that 39&#37; of patients treated with RTX for EGPA continued with GC requirements due to persistent asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Decreased values of peripheral blood eosinophil were reduced or normal after treatment with RTX regardless of the dosage regimen used&#44; in most patients&#46; This finding puts the close relationship that the different cells of the immune system&#44; and especially the strong Th2 lymphocyte interaction through the secretion of cytokines &#40;IL-4&#44; IL-5 and IL-13&#41;&#44; with the B cell and the subsequent production and secretion of eotaxin-1&#44; IgG4&#44; IgE and ANCA in perspective&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2&#44;24</span></a> IgE is elevated in the serum of patients with EGPA&#46; This immunoglobulin&#44; which is produced by plasma cells&#44; is bound to receptors &#40;Fc¿R1&#41; on the surface of eosinophils&#44; which&#44; by binding to antigen&#44; induces their involvement in the inflammatory response&#46; Furthermore&#44; eotaxin-1 participates in the recruitment of eosinophils to the site of inflamation&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> These mechanisms could explain in part the decline of eosinophils after treatment with RTX&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Circulating CD20&#43;lymphocytes after RTX use were undetectable and thus persisted for variable time&#46; The period until the repopulation of CD20&#43;B cells was not uniform and in some patients was not correlated with the clinical evolution of the disease&#46; In the RAVE<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> study&#44; a high percentage of patients had undetectable CD20&#43;B cell counts after the infusion of RTX &#40;as occurred in the group using CYP&#41; and the time to repopulation thereof was variable&#46; Of greater importance was the finding regarding the repopulation of CD20&#43;B lymphocytes as an isolated variable that did not predict the relapse risk in the individual patient&#46; However&#44; patients who after the use of RTX persisted with undetectable CD20&#43;B lymphocyte levels and negative ANCA were unlikely to relapse&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">ANCA are not the only pathogenic mechanism involved in the genesis of this vasculitis&#59; EGPA patients have a strong IgG4 response regardless of the status of ANCA&#59; evidence of a dialog between the B lymphocytes and eosinophils&#44; and the ability of the B cell to secrete eotaxin-1&#44; which is involved in the recruitment of eosinophils at sites of inflammation<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">24&#8211;26</span></a> could be another pathogenic mechanism involved in the response mediated by RTX&#59; therefore the fact that a patient is ANCA negative does not predict a failure to respond to treatment with RTX&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">RTX was well tolerated&#59; only 2 patients experienced adverse reactions during infusion&#46; Adverse events were minor&#44; usually respiratory infections in outpatient care&#46; No deaths directly attributed to RTX were reported&#46; This is consistent with the adverse effects reported in large series and extensive clinical studies demonstrating the safety of RTX in the treatment of AAV&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">5&#8211;8</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">The most commonly used treatment strategies were&#58; RTX 1000<span class="elsevierStyleHsp" style=""></span>mg every 15 days &#40;total 2 infusions&#41; and 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> of RTX per week &#40;total of 4 infusions&#41;&#46; Although both strategies were not formally compared&#44; they appear to be equally effective for the induction of remission in the AAV&#59; the expert recommendation on the use of RTX in AAV is to use both strategies interchangeably&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">This study has limitations&#58; the number of patients is small&#44; follow-up time is limited&#44; definitions of activity and damage were not uniform &#8211; only in some studies was the Birmingham Vasculitis Activity Score used&#44; and in different versions&#44; immunosuppressive drugs and use of RTX differed between patients&#46; In addition&#44; we did not find publications regarding EGPA patients who did not respond to RTX&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">However&#44; there is a widespread tendency to reconsider the standards of treatment for AAV&#44; including EGPA&#44; both in the induction as well as in the maintenance&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28&#44;29</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Finally&#44; RTX appears to be effective and safe for the treatment of refractory EGPA&#44; relapses or newly diagnosed&#44; independent ANCA status&#46; Randomized clinical trials are necessary to confirm this observation&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Protection of people and animals</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that this research did not perform experiments on humans or animals&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data privacy</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Right to privacy and informed consent</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of Interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "titulo" => "Abstract"
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              "identificador" => "abst0005"
              "titulo" => "Background"
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              "titulo" => "Objective"
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          "titulo" => "Resumen"
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              "identificador" => "abst0040"
              "titulo" => "M&#233;todos"
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              "titulo" => "Resultados"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and Methods"
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            0 => array:2 [
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          "titulo" => "Discussion"
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          "titulo" => "Ethical Responsibilities"
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            0 => array:2 [
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              "titulo" => "Protection of people and animals"
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              "identificador" => "sec0040"
              "titulo" => "Data privacy"
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              "identificador" => "sec0045"
              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Conflict of Interest"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2014-03-11"
    "fechaAceptado" => "2014-08-08"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec515320"
          "palabras" => array:3 [
            0 => "Rituximab"
            1 => "Eosinophilic granulomatosis with polyangiitis"
            2 => "Antineutrophil cytoplasmic antibodies associated vasculitis"
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        ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:3 [
            0 => "Rituximab"
            1 => "Granulomatosis eosinof&#237;lica con poliangitis"
            2 => "Vasculitis asociadas a anticuerpos anticitoplasma de neutr&#243;filo"
          ]
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The general consensus is that for patients with EGPA with poor prognosis&#44; intensive therapy with both GC and CF is indicated&#46; The maintenance of remission is made with GC and AZA&#46; A considerable number of patients with EGPA are refractory to first line therapy&#44; experience dose-limiting side effects or relapse&#46; In clinical trials&#44; RTX was effective for the treatment of ANCA-associated vasculitis&#46; However&#44; patients with a diagnosis of EGPA were not included&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To review and analyze the published literature regarding the use of RTX in the treatment of EGPA&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The literature search was performed in MEDLINE and LILACS from 1965 and 1986 respectively until February 2014&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">27 patients were included&#46; RTX treatment was due to refractory disease &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41;&#44; relapse &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; and with new diagnosis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46; The affected organs were the lungs&#44; peripheral nervous system&#44; kidney and the eyes&#46; Sixteen patients had clinical remission and 8 patients had clinical response&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">RTX was effective and well tolerated for the treatment of EGPA&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
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            "identificador" => "abst0010"
            "titulo" => "Objective"
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            "identificador" => "abst0015"
            "titulo" => "Methods"
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            "identificador" => "abst0020"
            "titulo" => "Results"
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            "titulo" => "Conclusions"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Algunos pacientes con granulomatosis eosinof&#237;lica con poliangitis &#40;EGPA&#41; y factores de mal pron&#243;stico son refractarios o presentan efectos adversos al tratamiento de inducci&#243;n &#40;glucocorticoides &#91;GC&#93; y ciclofosfamida &#91;CF&#93;&#41;&#44; o recaen durante el mantenimiento &#40;GC y azatioprina&#41;&#44; haciendo necesaria la b&#250;squeda de alternativas terap&#233;uticas&#46; En ensayos cl&#237;nicos&#44; el RTX demostr&#243; ser eficaz para el tratamiento de las vasculitis asociadas al ANCA&#59; sin embargo&#44; los pacientes con EGPA no fueron incluidos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Revisar y analizar la bibliograf&#237;a sobre la uso de RTX para el tratamiento de la EGPA&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La b&#250;squeda se realiz&#243; en MEDLINE y LILACS &#40;1965 y 1986&#44; respectivamente&#44; hasta febrero del 2014&#41;&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se incluy&#243; a 27 pacientes&#46; La indicaci&#243;n de RTX fue por enfermedad refractaria &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41;&#44; reca&#237;da &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; y nuevo diagn&#243;stico &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46; Los &#243;rganos afectados fueron los pulmones&#44; el sistema nervioso perif&#233;rico&#44; el ri&#241;&#243;n y los ojos&#46; Se observ&#243; remisi&#243;n en 16 y respuesta en 8 pacientes&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El RTX fue eficaz y bien tolerado para el tratamiento de la EGPA&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mu&#241;oz SA&#44; Gandino IJ&#44; Orden AO&#44; Allievi A&#46; Rituximab en el tratamiento de la granulomatosis eosinof&#237;lica con poliangitis&#46; Reumatol Clin&#46; 2015&#59;11&#58;165&#8211;169&#46;</p>"
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        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">AZA&#58; azathioprine&#59; CF&#58; cyclophosphamide&#59; CSP&#58; cyclosporin&#59; ND&#58; new diagnosis&#59; F&#58; female&#59; Ig&#58; immunoglobulin&#59; M&#58; male&#59; MFM&#58; mycohenolate mofetil&#59; MP&#58; methylprednisolone&#59; MTX&#58; methotrexate&#44; NA&#58; not applicable&#59; NR&#58; not reported&#59; PF&#58; plasmapheresis&#59; PS&#58; prednisone&#59; Rl&#58; relapse&#59; Rf&#58; refractory&#59; RP&#58; response&#59; RM&#58; remission&#59; CNS&#58; central nervous system&#59; PNS&#58; peripheral nervous system&#59; RTX&#58; rituximab&#59; UA&#58; upper airway&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient&#47;reference&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">Age&#47;gender&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">Status&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">Organs affected&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"><span class="elsevierStyleBold">Previous</span> and concomitant treatments&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">Time of follow up&#40;Months&#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&#46; of cyclesof RTX and indication&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">Result&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">Adverse events&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">1<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Skin&#44; lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> CF&#44; AZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pneumonia&#44; herpes zoster&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">2<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; PNS&#44; VAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> CF&#44; Ig&#44; MFM&#44; Alemtuzumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;relapse&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">3<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; VAS&#44; PNS&#44; articular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> CF&#44; AZA&#44; MFM&#44; INF Alemtuzumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Respiratory infection&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">4<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Skin&#44; kidney&#44; eye&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MP&#44; <span class="elsevierStyleBold">PS&#44; CF&#44;</span> PF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">5<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; heart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MP&#44; <span class="elsevierStyleBold">PS&#44;</span> Ig&#44; CF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">6<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; joints&#44; skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MP&#44; <span class="elsevierStyleBold">PS&#44;</span> CF&#44; Ig&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">7<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PS&#44; AZA&#44; MTX&#44; CF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bronchospasm&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">8<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Joint&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PS&#44; CF&#44; MFM&#44; AZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bronchospasm&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">9<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> CF&#44; <span class="elsevierStyleBold">MFM</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">10<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; ear&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> AZA&#44; <span class="elsevierStyleBold">MTX&#44;</span> CSP&#44; infliximab&#44; anakinra&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;prophylaxis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">11<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung VAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; AZA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;prophylaxis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">12<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; joint&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;relapse&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">13<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> CF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;relapse&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">14<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; kidney&#44; lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">15<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; kidney&#44; muscle&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">16<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; CF&#44;</span> AZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">17<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&#44; febrile syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MP&#44; <span class="elsevierStyleBold">PS&#44;</span> Ig&#44; CF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">18<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70&#47;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MP&#44; CF&#44; PF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">19<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; heart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; CF&#44; AZA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&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><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">20<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; heart&#44; PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; AZA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&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><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">21<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; PNS&#44; SNC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> MTX&#44; <span class="elsevierStyleBold">AZA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&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><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">22<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; heart&#44; CNS&#44; skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; CF&#44; AZA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;prophylaxis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">23<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; heart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; CF&#44; AZA</span> AZA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;prophylaxis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Seminoma&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">24<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; PNS&#44; skin&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44;</span> CF&#44; <span class="elsevierStyleBold">MFM&#44;</span> MTX&#44; LF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;prophylaxis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">25<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; heart&#44; skin&#44; PNS&#44; CNS&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; AZA&#44;</span> CF&#44; MTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&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><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">26<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rf&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; PNS&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; CF&#44; AZA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&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><td class="td" title="table-entry  " align="left" valign="top">RP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&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">27<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lung&#44; eye&#44; ear&#44; PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">PS&#44; MTX</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&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><td class="td" title="table-entry  " align="left" valign="top">RM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab784591.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">General Characteristics of the 27 EGPA Patients Treated With RTX Until February 2014&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "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="" 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">Patients studied&#47;total prior rituximab&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">Patients studied&#47;total after rituximab&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">ANCA&#47;specificity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&#47;27C &#40;&#43;&#41;&#58; 12&#37;P &#40;&#43;&#41;&#58; 46&#37;C and P &#40;&#8722;&#41;&#58; 42&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;27C &#40;&#43;&#41;&#58; 0&#37;P &#40;&#43;&#41;&#58; 10&#37;C and P &#40;&#8722;&#41;&#58; 90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Eosinophil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&#47;27High&#58; 100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&#47;27Descent&#58; 55&#37;Normal&#58; 45&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">CD20&#43;lymphocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#47;27Normal&#58; 100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#47;27Undetectable&#58; 100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Details of the Presence of ANCA&#44; Eosinophils and Lymphocytes CD20&#43; Before and After Treatment With RTX&#46;</p>"
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        "etiqueta" => "Table 3"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">NR&#58; not reported&#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="" 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">No&#46; patients &#40;M&#47;F&#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">Age&#40;years&#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">Meanfollow up&#40;months&#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">Indicationdisease&#40;No&#46;&#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">Responsen &#40;&#37;&#41;&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">Cases analyzed<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">9&#8211;21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 &#40;15&#47;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory &#40;20&#41;Relapse &#40;5&#41;New diag&#46; &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Remission&#58; 16 &#40;59&#41;Responded&#58; 8 &#40;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dubrau et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;NR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory &#40;5&#41;Relapse &#40;3&#41;New diag&#46; &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Remission&#58; 1 &#40;9&#41;Responded&#58; 7 &#40;64&#41;No response 1 &#40;9&#41;Lost&#58; 2 &#40;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Hot et al&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;16&#47;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Refractory or relapsed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Remission&#58; 26 &#40;88&#41;Responded&#58; 2 &#40;6&#41;No response&#58; 2 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab784590.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Details of Response to Treatment With RTX in EGPA Cases Analyzed and 2 Recent Series Reported in Abstracts&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:29 [
            0 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;C&#46; Jennette"
                            1 => "R&#46;J&#46; Falk"
                            2 => "P&#46;A&#46; Bacon"
                            3 => "N&#46; Basu"
                            4 => "M&#46;C&#46; Cid"
                            5 => "F&#46; Ferrario"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.37715"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2013"
                        "volumen" => "65"
                        "paginaInicial" => "1"
                        "paginaFinal" => "11"
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                            3 => "L&#46; de la Vara-Iniesta"
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2015.01.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	18	11	29
2024 October	69	33	102
2024 September	78	23	101
2024 August	104	31	135
2024 July	76	37	113
2024 June	73	34	107
2024 May	68	32	100
2024 April	59	17	76
2024 March	68	26	94
2024 February	47	23	70
2024 January	59	18	77
2023 December	44	21	65
2023 November	35	25	60
2023 October	47	27	74
2023 September	108	35	143
2023 August	37	10	47
2023 July	39	29	68
2023 June	43	29	72
2023 May	45	21	66
2023 April	34	8	42
2023 March	75	33	108
2023 February	55	34	89
2023 January	52	23	75
2022 December	78	29	107
2022 November	54	35	89
2022 October	66	40	106
2022 September	38	34	72
2022 August	35	41	76
2022 July	35	39	74
2022 June	38	31	69
2022 May	55	47	102
2022 April	68	54	122
2022 March	79	50	129
2022 February	51	32	83
2022 January	32	37	69
2021 December	47	35	82
2021 November	40	41	81
2021 October	56	61	117
2021 September	53	41	94
2021 August	45	48	93
2021 July	39	34	73
2021 June	55	48	103
2021 May	57	40	97
2021 April	96	101	197
2021 March	64	19	83
2021 February	52	25	77
2021 January	66	30	96
2020 December	57	32	89
2020 November	45	29	74
2020 October	19	14	33
2020 September	48	26	74
2020 August	45	28	73
2020 July	35	34	69
2020 June	39	26	65
2020 May	35	24	59
2020 April	33	19	52
2020 March	27	10	37
2018 May	2	0	2
2018 April	114	10	124
2018 March	143	6	149
2018 February	29	4	33
2018 January	30	10	40
2017 December	33	17	50
2017 November	38	12	50
2017 October	41	11	52
2017 September	29	12	41
2017 August	26	16	42
2017 July	40	19	59
2017 June	68	16	84
2017 May	64	17	81
2017 April	52	22	74
2017 March	38	14	52
2017 February	23	14	37
2017 January	34	17	51
2016 December	65	16	81
2016 November	38	9	47
2016 October	58	9	67
2016 September	75	8	83
2016 August	62	8	70
2016 July	32	11	43
2015 December	2	0	2
2015 November	1	34	35
2015 October	1	36	37
2015 September	1	0	1
2015 August	3	27	30
2015 July	31	10	41
2015 June	53	21	74
2015 May	71	38	109

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