Bronchiectasis, lymphadenopathies related to BAFF overexpression and lymphoplasmacytic cystitis as adverse events associated with prolonged use of rituximab in systemic autoimmune rheumatic diseases

Cañas, C.A.; Posso-Osorio, I.; Pérez-Uribe, V.; Erazo-Martínez, V.

doi:10.1016/j.rceng.2024.06.001

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"apellidos" => "Erazo-Martínez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Universidad Icesi, CIRAT: Centro de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Calle 18 No. 122 -135, Cali 760031, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidad Icesi, Facultad de Ciencias de la Salud, Calle 18 No. 122 -135, Cali 760031, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Fundación Valle del Lili, Unidad de Reumatología, Cra 98 No. 18 - 49, Cali 760032, Colombia" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Fundación Valle del Lili, Centro de Investigaciones Clínicas, Cra 98 No. 18 - 49, Cali 760032, Colombia" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Bronquiectasias, adenopatías relacionadas con la sobreexpresión de BAFF y cistitis linfoplasmocítica como eventos adversos asociados al uso prolongado de rituximab en enfermedades reumáticas autoinmunes sistémicas" ] ] "textoCompleto" => "IntroductionRituximab (RTX) is a chimeric IgG monoclonal antibody directed against the CD20 antigen expressed on normal and malignant B cells that is currently essential for treating various neoplastic, autoinflammatory, and autoimmune pathologies.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> RTX has a broad use in systemic autoimmune diseases (SAIDs), such as anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and rheumatoid arthritis (RA).<a class="elsevierStyleCrossRef" href="#bib0010">2</a> RTX is also indicated as a third-line treatment in systemic lupus erythematosus (SLE) and is used off-label in other SAIDs.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a>RTX is considered to have acceptable tolerability in the short and long term; after RTX treatment, circulating CD20+ cells are severely decreased, mainly due to antibody-mediated cytotoxicity.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> These cells are precursors to plasma cells and produce circulating immunoglobulin G (IgG). However, a greater effect on gamma globulin production occurs rarely; indeed, this was not a big issue in clinical trials of RTX for AAV or RA.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a>Infusion-related reactions are the most common adverse events (AE)s associated with RTX use and occur mainly due to the release of cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α).<a class="elsevierStyleCrossRef" href="#bib0040">8</a> The incidence of hypogammaglobulinemia following chronic use of RTX is rare and associated with viral and bacterial infections, and decreased response to vaccines.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Risk factors for developing hypogammaglobulinemia are accumulated doses, concomitant therapies, and comorbidities.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>AEs related to the long-term use of RTX are less recognized, aside from infectious processes related to hypogammaglobulinemia.In the present study, we analyzed a cohort of patients with SAIDs refractory to conventional treatments requiring chronic treatment with RTX. We reported the possible AEs related to this type of therapy.MethodsStudy design and patientsWe studied a cohort of patients with SAIDs from 2008 until 2022 at Fundación Valle del Lili, Cali, Colombia. Our cohort included 178 patients with refractory SAIDs undergoing RTX treatment. We identified patients' clinical and demographic characteristics, the frequency of possible AEs development after the long-term administration of RTX with emphasis on noninfectious AEs.An RTX cycle is defined as the application of 1 g of RTX intravenously on the first and fourteenth day. The patients were premedicated with prednisone 50 mg and paracetamol 1 g. RTX cycles were repeated every 6–12 months depending on the characteristics and evolution of the disease.AEs were classified using the Common Terminology Criteria for Adverse Events (CTCAE) of the National Institutes of Health (NIH). Grade 1 Mild: asymptomatic or mild symptoms, intervention not indicated. Grade 2 Moderate: minimal, local, or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization indicated. Grade 4 Life-threatening consequences: urgent intervention indicated. Grade 5: death related to AE.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>The possible AEs evaluated included IRRs (cytokine release syndrome, IgE-mediated or non-IgE-mediated hypersensitivity, serum sickness), hematologic AEs (neutropenia, hypogammaglobulinemia IgG, lymphadenopathy), pulmonary AEs (interstitial lung disease, hypersensitivity pneumonitis, bronchiectasis), urinary AEs (lymphoplasmacytic cystitis), and neurological AEs (progressive multifocal encephalopathy).The Institutional Ethics Committee approved the study (#2025). This study complies with the Declaration of Helsinki.Statistical analysisStatistical analyses were performed using Stata® version 14 (StataCorp, College Station, TX, USA). Quantitative variables are presented as the means (standard deviation) or medians (interquartile range).ResultsGeneral patient characteristicsFrom a cohort of 1006 patients with follow-up from 2008 to 2022, 178 patients (17.69%) who were given RTX as a treatment for their refractory SAIDs were analyzed. The patients’ median age at inclusion was 50.4 (36.5–54.5) years, and 152 (85.39%) were female. The most common SAID was RA (91, 51.12%), followed by SLE (52, 29.21%), inflammatory myopathies (IIM) (15, 8.42%), Sjögren’s syndrome (SS) (5, 2.80%), and AAV (5, 2.80%). Miscellaneous autoimmune neurological diseases occurred in 10 patients (5.61%), including transverse myelitis in 5 (2.80%), myasthenia gravis in 2 (1.12%), autoimmune encephalitis in 1 (0.56%), multiple sclerosis in 1 (0.56%) and giant cell arteritis with central nervous system involvement in 1 (0.56%).The median duration of the SAIDs was 13 (9–17) years. The mean age at first diagnosis was 37.6 (±17.2) years. The most common comorbidities were vitamin D deficiency (67, 37.64%), hypothyroidism (46, 25.84%), hypertension (40, 22.47%), dyslipidemia (15, 8.42%), diabetes (12, 6.74%), chronic kidney disease (2, 1.12%), chronic obstructive pulmonary disease (1, 0.56%), and coronary artery disease (1, 0.56%).RTX treatment characteristicsThe mean age at first RTX administration was 43.2 (±17.5) years. The median number of cycles administered was 4 (2–9) during a median time of 4 (1–6) years. Regarding the discontinuation cause of the drug, the first cause of discontinuation was secondary to AEs (52, 29.21%), followed by a lack of drug efficacy (24, 13.48%), disease remission (20, 11.23%), and loss of effectiveness over time (5, 2.80%).Adverse events related to RTXIn 47 patients (26.40%), 55 AEs related to RTX occurred. Eight patients had two AEs. 32 patients had IRRs: 21 (11.79%) had cytokine release syndrome, nine (5.05%) patients with IgE-mediated or non-IgE-mediated hypersensitivity, and two (1.12%) serum sickness disease. In the hematologic system, twelve (6.74%) presented hypogammaglobulinemia IgG, and three (1.6%) had lymphadenopathies with lymphoid follicular hyperplasia confirmed by biopsy. Other AEs included bronchiectasis (4, 2.24%) and lymphoplasmacytic cystitis (4, 2.2%). Interstitial lung disease, hypersensitivity pneumonitis, neutropenia, and progressive multifocal encephalopathy did not occur.Mortality occurred in three patients (1.68%): cytokine release syndrome presented in the second cycle of RTX in a 24-year-old male patient with RA, sepsis after urinary infection secondary to severe lymphoplasmacytic cystitis in an SLE 28-year-old female and severe development of bronchiectasis in 60-year-old females with RA.Possible long-term AEs and the degree of severity are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>DiscussionAn AE is defined as any medical event in a patient who was administered a medication that 1) appeared after its indication, 2) had no direct relationship to the underlying disease or other concomitant condition, and 3) was not attributable to the medication. However, attributing AEs to medications is complex and controversial.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> The present study identified AEs associated with RTX’s long-term use (several cycles) in SAIDs. It is challenging to make associations between a de novo clinical condition and medications in a patient with a SAID, considering that SAIDs can theoretically affect any organ or system. Physicians who treat this type of patient can better identify potential AEs by considering whether patients exhibit controlled disease or are in remission when a new clinical condition appears. Such de novo clinical manifestations related to AE do not resemble typical SAIDs manifestations.In the present study, we identify three possible AEs related to the long-term use of RTX in patients with SAIDs: lymphadenopathy secondary to lymphoid follicular hyperplasia, bronchiectasis, and a form of severe lymphoplasmacytic cystitis.Three patients with SLE and de novo development of lymphadenopathies were reported. SLE is a disease that can cause lymph node enlargement in up to a quarter of cases. However, “lymphadenopathy” (defined as an enlargement greater than 1 cm in the minor diameter for cervical and axillary LNs, ≥0.5 cm for iliac, popliteal, and epitrochlear LNs, and ≥1.5 cm for inguinal LNs) may be caused by illnesses other than SLE itself. A histological study is indispensable to achieve a precise diagnosis.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Two patients with SLE with several cycles of RTX developed a form of lymphoid follicular hyperplasia in whose biopsies we found overexpression of the B-cell activating factor belonging to the TNF family (BAFF) and its receptors. These patients had a favorable clinical response to using belimumab (an anti-BAFF drug). These results suggest a possible role in blocking CD20-positive cells and a compensatory increase in BAFF.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Adverse pulmonary reactions occur in up to 5.3% of cancer patients treated with RTX, including interstitial lung disease and hypersensitivity pneumonitis.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> A previous report describes the case of a 17-year-old patient who received RTX1 g every 6 months for 6 years for neuromyelitis optica, who developed rhinosinusitis and recurrent pneumonia with bronchiectasis in the context of hypogammaglobulinemia.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> In our series, four patients (two with RA, one with SLE, and one with IIM) presented bronchiectasis de novo with accelerated development of their symptoms. These patients had their underlying diseases controlled. One patient with SLE concomitantly developed hypogammaglobulinemia G. Once an AE was suspected, no new doses of RTX were administered. One patient died from severe respiratory symptoms. Our group previously reported three cases. The temporal relationship between treatment with RTX and respiratory complications such as chronic sinusitis, recurrent pneumonia, and the subsequent appearance of bronchiectasis may suggest a pathogenic connection.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> More studies are needed to corroborate this relationship and make more precise preventive or therapeutic recommendations.In this study, four patients with SLE developed a very severe form of cystitis. Bladder biopsies were performed where extensive lymphoplasmacytic infiltration was observed. The severity of this presentation is unusual in patients with SLE, in whom moderate autoimmune cystitis or “lupus cystitis” has been described.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Our patients presented severe dysuria, nocturia, polyuria, and perineal pain. These patients required prolonged hospitalization, during which different treatments were established, including high doses of corticosteroids. One of the patients died due to opportunistic infections.The possible cause of severe bronchiectasis and lymphoplasmacytic cystitis following RTX treatment is related to a predisposition to developing local infections (bronchial tubes, bladder), possibly due to impaired humoral and cellular immunity.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> In addition, a defect in the reparative processes of the bronchial wall<a class="elsevierStyleCrossRef" href="#bib0100">20</a> and bladder could be considered.ConclusionBronchiectasis, lymphoid follicular hyperplasia related to BAFF overexpression, and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX. The association between long-term use of RTX and these three described clinical conditions remains to be demonstrated, but this report suggests a cause for concern. The present work alerts physicians to these findings.FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Conflicts of interestNone.Ethical standardsThis study followed the ethical standards laid down in the 1964 Declaration of Helsinki. Approval for this study was obtained from Fundación Valle del Lili´s Institutional review board (IRB). Since there is no risk associated with this study, it was exempt from obtaining informed consent in compliance with Resolution 8430 issued by the Ministry of Health of Colombia." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2214936" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1856931" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2214937" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1856930" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design and patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "General patient characteristics" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "RTX treatment characteristics" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Adverse events related to RTX" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Ethical standards" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-12-01" "fechaAceptado" => "2024-04-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1856931" "palabras" => array:4 [ 0 => "Anti-CD 20" 1 => "Side effects" 2 => "Long-term adverse events" 3 => "Hypogammaglobulinemia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1856930" "palabras" => array:4 [ 0 => "Anti-CD 20" 1 => "Efectos secundarios" 2 => "Eventos adversos a largo plazo" 3 => "Hipogammaglobulinemia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe long-term use of rituximab (RTX) has been gaining ground in the treatment of systemic autoimmune diseases. The adverse events (AEs) associated with its use different to infections are being reported. MethodsA cohort of patients with SAIDs treated at a high-complexity center in Cali (southwestern Colombia) with follow-up from January 2008 to December 2022 were examined to search for potential AEs associated with prolonged use of RTX. ResultsFrom 178 patients with long-term use of RTX 3 (1.68%) had lymphadenopathies with lymphoid follicular hyperplasia related to BAFF overexpression, 4 (2.24%) with bronchiectasis, and 4 (2.24%) with lymphoplasmacytic cystitis. ConclusionBronchiectasis, lymphoid follicular hyperplasia related to BAFF overexpression, and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónEl uso a largo plazo de rituximab (RTX) ha ido ganando terreno en el tratamiento de varias enfermedades autoinmunes. Los eventos adversos (EA) asociados con su uso diferente a infecciones se han empezado a reporter. MétodosSe examinó a una cohorte de pacientes con EAS tratados en un centro de alta complejidad en Cali (suroccidente de Colombia) con seguimiento desde enero de 2008 hasta diciembre de 2022 para buscar posibles EA asociados al uso prolongado de RTX. ResultadosDe 178 pacientes con uso prolongado de RTX 3 (1.68%) presentaron adenopatías con hiperplasia folicular linfoide relacionada con la sobreexpresión BAFF, 4 (2.24%) con bronquiectasias) y 4 (2.24%) con cistitis linfoplasmocítica. ConclusiónLas bronquiectasias, la hiperplasia folicular linfoide relacionada con la sobreexpresión de BAFF y la cistitis linfoplasmocítica pueden ser EA a largo plazo en pacientes con uso prolongado de RTX." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "AE: adverse event." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AE \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Severity G: Grade<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypogammaglobulinemia IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 (6.74) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G1: 8 (4.49)G2: 0 (0.00)G3: 2 (1.12)G4: 2 (1.12)G5: 0 (0.00) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphadenopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (1.68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G1: 0 (0.00)G2: 3 (1,68)G3: 0 (0.00)G4: 0 (0.00)G5: 0 (0.00) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronchiectasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (2.24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G1: 0 (0.00)G2: 1 (0.56)G3: 2 (1.12)G4: 0 (0.00)G5: 1 (0.56) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphoplasmacytic cystitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (2.24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G1: 0 (0.00)G2: 1 (0.56)G3: 2 (1.12)G4: 0 (0.00)G5: 1 (0.56) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3612238.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "According to Common Terminology Criteria for Adverse Events (CTCAE) of the National Institutes of Health (NIH).<a class="elsevierStyleCrossRef" href="#bib0055">11</a>" ] ] ] "descripcion" => array:1 [ "en" => "Possible adverse events in a cohort of 178 patients with long-term rituximab (RTX) use, type of AE, number of cases, and severity." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G.L. 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        "titulo" => "Bronquiectasias&#44; adenopat&#237;as relacionadas con la sobreexpresi&#243;n de BAFF y cistitis linfoplasmoc&#237;tica como eventos adversos asociados al uso prolongado de rituximab en enfermedades reum&#225;ticas autoinmunes sist&#233;micas"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rituximab &#40;RTX&#41; is a chimeric IgG monoclonal antibody directed against the CD20 antigen expressed on normal and malignant B cells that is currently essential for treating various neoplastic&#44; autoinflammatory&#44; and autoimmune pathologies&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> RTX has a broad use in systemic autoimmune diseases &#40;SAIDs&#41;&#44; such as anti-neutrophil cytoplasmic antibody-associated vasculitis &#40;AAV&#41; and rheumatoid arthritis &#40;RA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> RTX is also indicated as a third-line treatment in systemic lupus erythematosus &#40;SLE&#41; and is used off-label in other SAIDs&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">RTX is considered to have acceptable tolerability in the short and long term&#59; after RTX treatment&#44; circulating CD20&#43; cells are severely decreased&#44; mainly due to antibody-mediated cytotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> These cells are precursors to plasma cells and produce circulating immunoglobulin G &#40;IgG&#41;&#46; However&#44; a greater effect on gamma globulin production occurs rarely&#59; indeed&#44; this was not a big issue in clinical trials of RTX for AAV or RA&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Infusion-related reactions are the most common adverse events &#40;AE&#41;s associated with RTX use and occur mainly due to the release of cytokines such as interleukin &#40;IL&#41;-6 and tumor necrosis factor-alpha &#40;TNF-&#945;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The incidence of hypogammaglobulinemia following chronic use of RTX is rare and associated with viral and bacterial infections&#44; and decreased response to vaccines&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Risk factors for developing hypogammaglobulinemia are accumulated doses&#44; concomitant therapies&#44; and comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">AEs related to the long-term use of RTX are less recognized&#44; aside from infectious processes related to hypogammaglobulinemia&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the present study&#44; we analyzed a cohort of patients with SAIDs refractory to conventional treatments requiring chronic treatment with RTX&#46; We reported the possible AEs related to this type of therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design and patients</span><p id="par0030" class="elsevierStylePara elsevierViewall">We studied a cohort of patients with SAIDs from 2008 until 2022 at Fundaci&#243;n Valle del Lili&#44; Cali&#44; Colombia&#46; Our cohort included 178 patients with refractory SAIDs undergoing RTX treatment&#46; We identified patients&#39; clinical and demographic characteristics&#44; the frequency of possible AEs development after the long-term administration of RTX with emphasis on noninfectious AEs&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">An RTX cycle is defined as the application of 1&#8239;g of RTX intravenously on the first and fourteenth day&#46; The patients were premedicated with prednisone 50&#8239;mg and paracetamol 1&#8239;g&#46; RTX cycles were repeated every 6&#8211;12 months depending on the characteristics and evolution of the disease&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">AEs were classified using the Common Terminology Criteria for Adverse Events &#40;CTCAE&#41; of the National Institutes of Health &#40;NIH&#41;&#46; Grade 1 Mild&#58; asymptomatic or mild symptoms&#44; intervention not indicated&#46; Grade 2 Moderate&#58; minimal&#44; local&#44; or noninvasive intervention indicated&#46; Grade 3 Severe or medically significant but not immediately life-threatening&#59; hospitalization indicated&#46; Grade 4 Life-threatening consequences&#58; urgent intervention indicated&#46; Grade 5&#58; death related to AE&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The possible AEs evaluated included IRRs &#40;cytokine release syndrome&#44; IgE-mediated or non-IgE-mediated hypersensitivity&#44; serum sickness&#41;&#44; hematologic AEs &#40;neutropenia&#44; hypogammaglobulinemia IgG&#44; lymphadenopathy&#41;&#44; pulmonary AEs &#40;interstitial lung disease&#44; hypersensitivity pneumonitis&#44; bronchiectasis&#41;&#44; urinary AEs &#40;lymphoplasmacytic cystitis&#41;&#44; and neurological AEs &#40;progressive multifocal encephalopathy&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The Institutional Ethics Committee approved the study &#40;&#35;2025&#41;&#46; This study complies with the Declaration of Helsinki&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Statistical analyses were performed using Stata&#174; version 14 &#40;StataCorp&#44; College Station&#44; TX&#44; USA&#41;&#46; Quantitative variables are presented as the means &#40;standard deviation&#41; or medians &#40;interquartile range&#41;&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">General patient characteristics</span><p id="par0060" class="elsevierStylePara elsevierViewall">From a cohort of 1006 patients with follow-up from 2008 to 2022&#44; 178 patients &#40;17&#46;69&#37;&#41; who were given RTX as a treatment for their refractory SAIDs were analyzed&#46; The patients&#8217; median age at inclusion was 50&#46;4 &#40;36&#46;5&#8211;54&#46;5&#41; years&#44; and 152 &#40;85&#46;39&#37;&#41; were female&#46; The most common SAID was RA &#40;91&#44; 51&#46;12&#37;&#41;&#44; followed by SLE &#40;52&#44; 29&#46;21&#37;&#41;&#44; inflammatory myopathies &#40;IIM&#41; &#40;15&#44; 8&#46;42&#37;&#41;&#44; Sj&#246;gren&#8217;s syndrome &#40;SS&#41; &#40;5&#44; 2&#46;80&#37;&#41;&#44; and AAV &#40;5&#44; 2&#46;80&#37;&#41;&#46; Miscellaneous autoimmune neurological diseases occurred in 10 patients &#40;5&#46;61&#37;&#41;&#44; including transverse myelitis in 5 &#40;2&#46;80&#37;&#41;&#44; myasthenia gravis in 2 &#40;1&#46;12&#37;&#41;&#44; autoimmune encephalitis in 1 &#40;0&#46;56&#37;&#41;&#44; multiple sclerosis in 1 &#40;0&#46;56&#37;&#41; and giant cell arteritis with central nervous system involvement in 1 &#40;0&#46;56&#37;&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The median duration of the SAIDs was 13 &#40;9&#8211;17&#41; years&#46; The mean age at first diagnosis was 37&#46;6 &#40;&#177;17&#46;2&#41; years&#46; The most common comorbidities were vitamin D deficiency &#40;67&#44; 37&#46;64&#37;&#41;&#44; hypothyroidism &#40;46&#44; 25&#46;84&#37;&#41;&#44; hypertension &#40;40&#44; 22&#46;47&#37;&#41;&#44; dyslipidemia &#40;15&#44; 8&#46;42&#37;&#41;&#44; diabetes &#40;12&#44; 6&#46;74&#37;&#41;&#44; chronic kidney disease &#40;2&#44; 1&#46;12&#37;&#41;&#44; chronic obstructive pulmonary disease &#40;1&#44; 0&#46;56&#37;&#41;&#44; and coronary artery disease &#40;1&#44; 0&#46;56&#37;&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">RTX treatment characteristics</span><p id="par0070" class="elsevierStylePara elsevierViewall">The mean age at first RTX administration was 43&#46;2 &#40;&#177;17&#46;5&#41; years&#46; The median number of cycles administered was 4 &#40;2&#8211;9&#41; during a median time of 4 &#40;1&#8211;6&#41; years&#46; Regarding the discontinuation cause of the drug&#44; the first cause of discontinuation was secondary to AEs &#40;52&#44; 29&#46;21&#37;&#41;&#44; followed by a lack of drug efficacy &#40;24&#44; 13&#46;48&#37;&#41;&#44; disease remission &#40;20&#44; 11&#46;23&#37;&#41;&#44; and loss of effectiveness over time &#40;5&#44; 2&#46;80&#37;&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Adverse events related to RTX</span><p id="par0075" class="elsevierStylePara elsevierViewall">In 47 patients &#40;26&#46;40&#37;&#41;&#44; 55 AEs related to RTX occurred&#46; Eight patients had two AEs&#46; 32 patients had IRRs&#58; 21 &#40;11&#46;79&#37;&#41; had cytokine release syndrome&#44; nine &#40;5&#46;05&#37;&#41; patients with IgE-mediated or non-IgE-mediated hypersensitivity&#44; and two &#40;1&#46;12&#37;&#41; serum sickness disease&#46; In the hematologic system&#44; twelve &#40;6&#46;74&#37;&#41; presented hypogammaglobulinemia IgG&#44; and three &#40;1&#46;6&#37;&#41; had lymphadenopathies with lymphoid follicular hyperplasia confirmed by biopsy&#46; Other AEs included bronchiectasis &#40;4&#44; 2&#46;24&#37;&#41; and lymphoplasmacytic cystitis &#40;4&#44; 2&#46;2&#37;&#41;&#46; Interstitial lung disease&#44; hypersensitivity pneumonitis&#44; neutropenia&#44; and progressive multifocal encephalopathy did not occur&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Mortality occurred in three patients &#40;1&#46;68&#37;&#41;&#58; cytokine release syndrome presented in the second cycle of RTX in a 24-year-old male patient with RA&#44; sepsis after urinary infection secondary to severe lymphoplasmacytic cystitis in an SLE 28-year-old female and severe development of bronchiectasis in 60-year-old females with RA&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Possible long-term AEs and the degree of severity are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">An AE is defined as any medical event in a patient who was administered a medication that 1&#41; appeared after its indication&#44; 2&#41; had no direct relationship to the underlying disease or other concomitant condition&#44; and 3&#41; was not attributable to the medication&#46; However&#44; attributing AEs to medications is complex and controversial&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The present study identified AEs associated with RTX&#8217;s long-term use &#40;several cycles&#41; in SAIDs&#46; It is challenging to make associations between a de novo clinical condition and medications in a patient with a SAID&#44; considering that SAIDs can theoretically affect any organ or system&#46; Physicians who treat this type of patient can better identify potential AEs by considering whether patients exhibit controlled disease or are in remission when a new clinical condition appears&#46; Such de novo clinical manifestations related to AE do not resemble typical SAIDs manifestations&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the present study&#44; we identify three possible AEs related to the long-term use of RTX in patients with SAIDs&#58; lymphadenopathy secondary to lymphoid follicular hyperplasia&#44; bronchiectasis&#44; and a form of severe lymphoplasmacytic cystitis&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Three patients with SLE and de novo development of lymphadenopathies were reported&#46; SLE is a disease that can cause lymph node enlargement in up to a quarter of cases&#46; However&#44; &#8220;lymphadenopathy&#8221; &#40;defined as an enlargement greater than 1&#8239;cm in the minor diameter for cervical and axillary LNs&#44; &#8805;0&#46;5&#8239;cm for iliac&#44; popliteal&#44; and epitrochlear LNs&#44; and &#8805;1&#46;5&#8239;cm for inguinal LNs&#41; may be caused by illnesses other than SLE itself&#46; A histological study is indispensable to achieve a precise diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Two patients with SLE with several cycles of RTX developed a form of lymphoid follicular hyperplasia in whose biopsies we found overexpression of the B-cell activating factor belonging to the TNF family &#40;BAFF&#41; and its receptors&#46; These patients had a favorable clinical response to using belimumab &#40;an anti-BAFF drug&#41;&#46; These results suggest a possible role in blocking CD20-positive cells and a compensatory increase in BAFF&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Adverse pulmonary reactions occur in up to 5&#46;3&#37; of cancer patients treated with RTX&#44; including interstitial lung disease and hypersensitivity pneumonitis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> A previous report describes the case of a 17-year-old patient who received RTX1&#8239;g every 6 months for 6 years for neuromyelitis optica&#44; who developed rhinosinusitis and recurrent pneumonia with bronchiectasis in the context of hypogammaglobulinemia&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In our series&#44; four patients &#40;two with RA&#44; one with SLE&#44; and one with IIM&#41; presented bronchiectasis de novo with accelerated development of their symptoms&#46; These patients had their underlying diseases controlled&#46; One patient with SLE concomitantly developed hypogammaglobulinemia G&#46; Once an AE was suspected&#44; no new doses of RTX were administered&#46; One patient died from severe respiratory symptoms&#46; Our group previously reported three cases&#46; The temporal relationship between treatment with RTX and respiratory complications such as chronic sinusitis&#44; recurrent pneumonia&#44; and the subsequent appearance of bronchiectasis may suggest a pathogenic connection&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> More studies are needed to corroborate this relationship and make more precise preventive or therapeutic recommendations&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In this study&#44; four patients with SLE developed a very severe form of cystitis&#46; Bladder biopsies were performed where extensive lymphoplasmacytic infiltration was observed&#46; The severity of this presentation is unusual in patients with SLE&#44; in whom moderate autoimmune cystitis or &#8220;lupus cystitis&#8221; has been described&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Our patients presented severe dysuria&#44; nocturia&#44; polyuria&#44; and perineal pain&#46; These patients required prolonged hospitalization&#44; during which different treatments were established&#44; including high doses of corticosteroids&#46; One of the patients died due to opportunistic infections&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The possible cause of severe bronchiectasis and lymphoplasmacytic cystitis following RTX treatment is related to a predisposition to developing local infections &#40;bronchial tubes&#44; bladder&#41;&#44; possibly due to impaired humoral and cellular immunity&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In addition&#44; a defect in the reparative processes of the bronchial wall<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and bladder could be considered&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusion</span><p id="par0120" class="elsevierStylePara elsevierViewall">Bronchiectasis&#44; lymphoid follicular hyperplasia related to BAFF overexpression&#44; and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX&#46; The association between long-term use of RTX and these three described clinical conditions remains to be demonstrated&#44; but this report suggests a cause for concern&#46; The present work alerts physicians to these findings&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0125" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethical standards</span><p id="par0135" class="elsevierStylePara elsevierViewall">This study followed the ethical standards laid down in the 1964 Declaration of Helsinki&#46; Approval for this study was obtained from Fundaci&#243;n Valle del Lili&#180;s Institutional review board &#40;IRB&#41;&#46; Since there is no risk associated with this study&#44; it was exempt from obtaining informed consent in compliance with Resolution 8430 issued by the Ministry of Health of Colombia&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The long-term use of rituximab &#40;RTX&#41; has been gaining ground in the treatment of systemic autoimmune diseases&#46; The adverse events &#40;AEs&#41; associated with its use different to infections are being reported&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A cohort of patients with SAIDs treated at a high-complexity center in Cali &#40;southwestern Colombia&#41; with follow-up from January 2008 to December 2022 were examined to search for potential AEs associated with prolonged use of RTX&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">From 178 patients with long-term use of RTX 3 &#40;1&#46;68&#37;&#41; had lymphadenopathies with lymphoid follicular hyperplasia related to BAFF overexpression&#44; 4 &#40;2&#46;24&#37;&#41; with bronchiectasis&#44; and 4 &#40;2&#46;24&#37;&#41; with lymphoplasmacytic cystitis&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Bronchiectasis&#44; lymphoid follicular hyperplasia related to BAFF overexpression&#44; and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El uso a largo plazo de rituximab &#40;RTX&#41; ha ido ganando terreno en el tratamiento de varias enfermedades autoinmunes&#46; Los eventos adversos &#40;EA&#41; asociados con su uso diferente a infecciones se han empezado a reporter&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se examin&#243; a una cohorte de pacientes con EAS tratados en un centro de alta complejidad en Cali &#40;suroccidente de Colombia&#41; con seguimiento desde enero de 2008 hasta diciembre de 2022 para buscar posibles EA asociados al uso prolongado de RTX&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">De 178 pacientes con uso prolongado de RTX 3 &#40;1&#46;68&#37;&#41; presentaron adenopat&#237;as con hiperplasia folicular linfoide relacionada con la sobreexpresi&#243;n BAFF&#44; 4 &#40;2&#46;24&#37;&#41; con bronquiectasias&#41; y 4 &#40;2&#46;24&#37;&#41; con cistitis linfoplasmoc&#237;tica&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Las bronquiectasias&#44; la hiperplasia folicular linfoide relacionada con la sobreexpresi&#243;n de BAFF y la cistitis linfoplasmoc&#237;tica pueden ser EA a largo plazo en pacientes con uso prolongado de RTX&#46;</p></span>"
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            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">AE&#58; adverse event&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t">Hypogammaglobulinemia IgG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">12 &#40;6&#46;74&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">G1&#58; 8 &#40;4&#46;49&#41;G2&#58; 0 &#40;0&#46;00&#41;G3&#58; 2 &#40;1&#46;12&#41;G4&#58; 2 &#40;1&#46;12&#41;G5&#58; 0 &#40;0&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Lymphadenopathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3 &#40;1&#46;68&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">G1&#58; 0 &#40;0&#46;00&#41;G2&#58; 3 &#40;1&#44;68&#41;G3&#58; 0 &#40;0&#46;00&#41;G4&#58; 0 &#40;0&#46;00&#41;G5&#58; 0 &#40;0&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Bronchiectasis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4 &#40;2&#46;24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">G1&#58; 0 &#40;0&#46;00&#41;G2&#58; 1 &#40;0&#46;56&#41;G3&#58; 2 &#40;1&#46;12&#41;G4&#58; 0 &#40;0&#46;00&#41;G5&#58; 1 &#40;0&#46;56&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Lymphoplasmacytic cystitis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4 &#40;2&#46;24&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">G1&#58; 0 &#40;0&#46;00&#41;G2&#58; 1 &#40;0&#46;56&#41;G3&#58; 2 &#40;1&#46;12&#41;G4&#58; 0 &#40;0&#46;00&#41;G5&#58; 1 &#40;0&#46;56&#41;&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">According to Common Terminology Criteria for Adverse Events &#40;CTCAE&#41; of the National Institutes of Health &#40;NIH&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Possible adverse events in a cohort of 178 patients with long-term rituximab &#40;RTX&#41; use&#44; type of AE&#44; number of cases&#44; and severity&#46;</p>"
        ]
      ]
    ]
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:20 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rituximab&#58; a review of its use in non-Hodgkin&#8217;s lymphoma and chronic lymphocytic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "G&#46;L&#46; Plosker"
                            1 => "D&#46;P&#46; Figgitt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/00003495-200363080-00005"
                      "Revista" => array:7 [
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                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12662126"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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                      "autores" => array:1 [
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                          "etal" => false
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                            1 => "A&#46; Radbruch"
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                  "host" => array:1 [
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            2 => array:3 [
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                        0 => array:2 [
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                            0 => "C&#46; Galarza"
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                            3 => "L&#46; Zurita"
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                        ]
                      ]
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                  "host" => array:1 [
                    0 => array:2 [
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            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Off-label use of rituximab in a multipayer insurance system"
                      "autores" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21731512"
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                  "contribucion" => array:1 [
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                      "titulo" => "Rituximab&#44; an anti-cd20 monoclonal antibody&#58; history and mechanism of action"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "M&#46;D&#46; Pescovitz"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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            5 => array:3 [
              "identificador" => "bib0030"
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              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                        0 => array:2 [
                          "etal" => true
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                            0 => "J&#46;C&#46; Edwards"
                            1 => "L&#46; Szczepanski"
                            2 => "J&#46; Szechinski"
                            3 => "A&#46; Filipowicz-Sosnowska"
                            4 => "P&#46; Emery"
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                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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            6 => array:3 [
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                          "etal" => true
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                            1 => "P&#46;A&#46; Merkel"
                            2 => "P&#46; Seo"
                            3 => "R&#46; Spiera"
                            4 => "C&#46;A&#46; Langford"
                            5 => "G&#46;S&#46; Hoffman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1213277"
                      "Revista" => array:7 [
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              "identificador" => "bib0040"
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                  "contribucion" => array:1 [
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                          "etal" => false
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                    0 => array:2 [
                      "doi" => "10.1016/j.iac.2017.01.012"
                      "Revista" => array:7 [
                        "tituloSerie" => "Immunol Allergy Clin North Am"
                        "fecha" => "2017"
                        "volumen" => "37"
                        "numero" => "2"
                        "paginaInicial" => "397"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rituximab-associated hypogammaglobulinemia in autoimmune rheumatic diseases&#58; a single-center retrospective cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;D&#46; Wade"
                            1 => "V&#46;C&#46; Kyttaris"
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                    ]
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