Interferencia positiva de las paraproteínas en la determinación de bilirrubina total y su rol en el diagnóstico de gammapatías monoclonales / Positive interference of paraproteins in the determination of total bilirubin and its role in the diagnosis of monoclonal gammopathies / Interferência positiva de paraproteínas na determinação da bilirrubina total e seu papel no diagnóstico de gamopatias monoclonais

Resumen La interferencia por paraproteínas en los análisis clínicos ha sido extensamente informada a nivel mundial. Si bien se han propuesto estrategias metodológicas para evitar el informe de datos erróneos asociados a interferencias (p. ej. confirmación manual, sistema de alerta), en pocos casos se ha propuesto su detección como herramienta diagnóstica de patologías no sospechadas desde la clínica. A partir del trabajo conjunto de dos hospitales de la provincia de Buenos Aires se describió: i) la presencia de interferencia positiva de paraproteínas en la determinación de bilirrubina total con reactivos y autoanalizadores Wiener, y ii) su contribución, en un período inferior a los seis meses, a la detección de cuatro gammapatías no sospechadas (tres monoclonales). Se recomienda dar difusión de esta inferencia a nivel nacional y se propone un esquema de trabajo en laboratorio para identificar la interferencia así como un perfil mínimo de determinaciones para evaluar la existencia de gammapatías desconocidas.

Abstract Paraprotein interference in clinical biochemistry has been widely reported around the world. Methodological strategies have been proposed to avoid reporting erroneous data due to interferences (i.e. manual check, alert system); however, few cases have suggested its use as a diagnostic tool for unsuspected pathologies. Based on the joint work of two hospitals from Buenos Aires Province, the following has been described: i) the presence of positive interference of paraproteins in the assessment of total bilirubin with Wiener chemistry and autoanalizers, and ii) its contribution, in less than six months, to the diagnosis of four gammophaties previously unsuspected (three monoclonal ones). Sharing the occurrence of this interference in our country is recommended. An interference identification workflow is also propose, as well as a set of biochemical assays to evaluate the occurrence of unsuspected gammophaties.

Resumo A interferência da paraproteína na bioquímica clínica tem sido amplamente relatada em todo o mundo. Embora estratégias metodológicas para evitar a comunicação de dados errôneos associados a interferências tenham sido propostas (p. ex., verificação manual, sistema de alerta), em poucos casos sugerem seu uso como ferramenta diagnóstica para patologias não suspeitas a partir da clínica. Com base no trabalho conjunto de dois hospitais da Província de Buenos Aires, foi descrita: i) a presença de interferência positiva de paraproteínas na determinação da bilirrubina total com reagentes e autoanalisadores Wiener e ii) sua contribuição, em um período inferior aos seis meses, para o diagnóstico de quatro gamopatias não suspeitas (três monoclonais). Recomenda-se difundir essa interferência em nível nacional e se propõe um esquema de trabalho em laboratório para identificar a interferência bem como um perfil mínimo de determinações para avaliar a ocorrência de gamopatias desconhecidas.

Adesão e persistência ao tratamento com infliximabe: análise de uma coorte de um programa de suporte ao paciente no Brasil / Adherence and persistence to treatment with infliximab: analysis of a patient support program cohort in brazil

ABSTRACT Background: Monoclonal antibodies have proven efficacy in the management of several conditions and infliximab (IFX) is one of the most important drugs of the class. Some recent data have shown low rates of both persistence and adherence to several available biologics. Objective: The objective of this study was to describe adherence and persistence rate to IFX treatment and also persistence in the patient support program (PSP), among patients diagnosed with inflammatory bowel diseases (IBD) or rheumatic diseases (RD) enrolled in the program of a large pharmaceutical company in Brazil. Methods: Retrospective observational analysis using the PSP database. IBD or RD patients using IFX enrolled on the PSP database between September 2015 and August 2019 were retrospectively evaluated to identify the persistence rate and adherence and followed up until March 1, 2020. Patients were excluded if treatment start date was prior to program entry; first infusion prior to September 1st, 2015 or after August 31st, 2019; the patients did not started treatment; and patients with "OTHERS" in "Indication" field. Persistence was assessed considering both persistence in the program ("PSP persistence") and persistence on IFX in the PSP ("IFX persistence in the PSP"). PSP persistence was defined as the proportion of patients remaining in the program at 6, 12, 24, 36 and 48 months after initiating IFX. To determine IFX persistence in the PSP, censoring was defined at the time the patient left the program, died, or was lost to follow-up. Adherence to treatment was measured by medication possession ratio ((MPR) - All days supply / elapsed days from first prescription to last day of medication possession)). Descriptive statistics were initially used. Kaplan-Meier curve, the median time estimated by the survival function, Cox regression model, and restricted mean survival time (RMST) were used to evaluate the treatment persistence time at 24 months and the logistic regression model was performed aiming to identify variables associated with adherence (MPR ≥80%). Results: A total of 10,233 patients were analyzed, 5,826 (56.9%) with the diagnosis of RD and 4,407 (43.1%) of IBD. At the end of the follow-up (median 9.1 months from PSP entry to the last infusion), persistence in the PSP was 65.6%, 48.2%, 31.0%, 20.7% and 13.1% at 6, 12, 24, 36 and 48 months, respectively. Considering persistence on IFX in the PSP, estimates were 93.7%, 87.8%, 77.0%, 62.4% and 53.0% at 6, 12, 24, 36 and 48 months, respectively. Variables associated with the risk of non-persistence were gender, country region and diagnosis of rheumatoid arthritis and ankylosing spondylitis. Median MPR was 94.2%, while the percentage of patients with MPR ≥80% was 91.0%. Variables associated with MPR≥80% were country region and diagnosis of Crohn's disease. Conclusion: Many patients leave the program without discontinuing IFX, since the 12-month persistence were very different between program and medication estimates, while high adherence rates were observed among patients enrolled in the PSP. Data highlights the benefits of a PSP.

RESUMO Contexto: Os anticorpos monoclonais têm eficácia comprovada no manejo de diversas condições e o infliximabe (IFX) é um dos medicamentos mais importantes da classe. Alguns dados recentes demonstram baixas taxas de persistência e adesão a vários dos biológicos disponíveis. Objetivo: O objetivo deste estudo foi descrever a adesão e persistência ao tratamento com IFX e a persistência no programa de suporte ao paciente (PSP), entre pacientes diagnosticados com doenças inflamatórias intestinais (DII) ou doenças reumáticas (DR) inscritos no PSP de uma grande indústria farmacêutica no Brasil. Métodos: Análise observacional retrospectiva utilizando o banco de dados do PSP. Pacientes com DII ou DR usando IFX inscritos no banco de dados do PSP entre setembro de 2015 e agosto de 2019 foram avaliados retrospectivamente para identificar a taxa de persistência e adesão e acompanhados até 1º de março de 2020. Os pacientes foram excluídos se a data de início do tratamento fosse anterior à entrada no programa; primeira infusão antes de 1º de setembro de 2015 ou após 31 de agosto de 2019; o paciente não iniciou o tratamento; e pacientes com "OUTROS" no campo "indicação". A persistência foi avaliada considerando tanto a persistência no programa ("persistência PSP") quanto a persistência em uso de infliximabe no PSP ("persistência IFX no PSP"). A persistência no PSP foi definida como a proporção de pacientes que permaneceram no programa aos 6, 12, 24, 36 e 48 meses após o início do IFX. Para determinar a persistência do IFX no PSP, a censura foi definida quando o paciente deixou o programa, morreu ou perdeu o acompanhamento. A adesão ao tratamento foi medida pela razão de posse do medicamento (MPR)): todos os dias de fornecimento / decorridos da primeira prescrição ao último dia de posse do medicamento). A estatística descritiva foi inicialmente utilizada. A curva de Kaplan-Meier, o tempo mediano estimado pela função de sobrevida, o modelo de regressão de Cox e o tempo de sobrevida médio restrito (RMST) foram utilizados para avaliar o tempo de persistência do tratamento em 24 meses e o modelo de regressão logística foi realizado para identificar variáveis associadas à adesão (MPR ≥80%). Resultados: Foram analisados 10.233 pacientes, 5.826 (56,9%) com diagnóstico de DR e 4.407 (43,1%) de DII. Ao final do seguimento (mediana de 9,1 meses desde a entrada no PSP até a última infusão), a persistência no PSP foi de 65,6%, 48,2%, 31,0%, 20,7% e 13,1% aos 6, 12, 24, 36 e 48 meses, respectivamente. Considerando a persistência no IFX no PSP, as estimativas foram de 93,7%, 87,8%, 77,0%, 62,4% e 53,0% aos 6, 12, 24, 36 e 48 meses, respectivamente. As variáveis associadas ao risco de não persistência foram sexo, região do país e diagnóstico de artrite reumatoide e espondilite anquilosante. A mediana do MPR foi de 94,2%, enquanto o percentual de pacientes com MPR ≥80% foram de 91,0%. As variáveis associadas a MPR ≥80% foram região do país e diagnóstico de doença de Crohn. Conclusão: Muitos pacientes abandonam o programa sem interromper o IFX, pois a persistência em 12 meses foi muito diferente entre as estimativas do programa e da medicação, enquanto altas taxas de adesão foram observadas entre os pacientes inscritos no PSP. Os dados destacam os benefícios de um PSP.

Emicizumab prophylaxis in people with hemophilia A and inhibitors: a systematic review and meta-analysis

ABSTRACT BACKGROUND: Until recently, the treatment of people with hemophilia A and inhibitors (PwHAi) was based on the use of bypassing agents (BPA). However, the advent of emicizumab as prophylaxis has demonstrated promising results. OBJECTIVES: We aimed to compare the bleeding endpoints between PwHAi on BPA and those on emicizumab prophylaxis. DESIGN AND SETTING: Systematic review of interventions and meta-analysis conducted at the Universidade Federal de Goiás, Goiânia, Goiás, Brazil. METHODS: The CENTRAL, MEDLINE, Scopus, and LILACS databases were searched on February 21, 2023. Two authors conducted the literature search, publication selection, and data extraction. The selected publications evaluated the bleeding endpoints between PwHAi on emicizumab prophylaxis and those on BPA prophylaxis. The risk of bias was evaluated according to the Joanna Briggs Institute criteria. A meta-analysis was performed to determine the annualized bleeding rate (ABR) for treated bleeds. RESULTS: Five publications (56 PwHAi) were selected from the 543 retrieved records. Overall, bleeding endpoints were lower during emicizumab prophylaxis than during BPA prophylaxis. All the publications had at least one risk of bias. The only common parameter for the meta-analysis was the ABR for treated bleeds. During emicizumab prophylaxis, the ABR for treated bleeds was lower than during BPA prophylaxis (standard mean difference: −1.58; 95% confidence interval −2.50, −0.66, P = 0.0008; I2 = 68.4%, P = 0.0031). CONCLUSION: Emicizumab was superior to BPA in bleeding prophylaxis in PwHAi. However, both the small population size and potential risk of bias should be considered when evaluating these results. SYSTEMATIC REVIEW REGISTRATION: CRD42021278726, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278726.

Research advances in monoclonal antibodies for treatment of drug resistance in inflammatory bowel disease / 中国生物制品学杂志

@#Inflammatory bowel disease(IBD)is a complex inflammatory disease mediated by immunity that is treated with the goal of maintaining disease remission and preventing recurrence. With the deep study of the molecular mechanism of the occurrence and development of IBD,many related target molecules have been found,and the monoclonal antibodies of corresponding targets have been used to treat the disease,while the drug resistance phenomenon generated during treatment has seriously affected the treatment effect. In this paper,monoclonal antibodies such as infliximab were reviewed for the treatment of IBD resistance,with a view to understanding its possible mechanisms and exploring effective treatments and preventive measures

Research progress of biological agents in thyroid-associated ophthalmopathy / 国际眼科杂志(Guoji Yanke Zazhi)

Thyroid-associated ophthalmopathy(TAO)is a rare organ-specific autoimmune disease with an unclear pathogenesis. At present, the treatment still relies mainly on glucocorticoids and traditional immunosuppressants. However, some patients respond poorly to these drugs and experience treatment-related adverse reactions, highlighting the urgent need for novel drugs for TAO treatment. In recent years, with the deepening of research on the pathogenesis of TAO, a multitude of biologics targeting specific targets have emerged. Among them, teprotumumab, which targets the insulin-like growth factor-I receptor(IGF-IR), has been approved by the Food and Drug Administration for the treatment of TAO, and several other biologics are currently in clinical trials. This review provides the latest reference for the clinical prevention, treatment, and research of TAO by summarizing the current clinical research status of biologics targeting IGF-IR, neonatal Fc receptor(FcRn), thyroid-stimulating hormone receptor(TSHR), B cells, cytokines, and other biological agents in TAO and analyzing their impact on clinical treatment and future research trends.

Application of immunotherapy in relapsed/refractory B-cell acute lymphoblastic leukemia / 中国药房

Immunotherapy， as an emerging treatment method， has been proven to improve the prognosis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia （B-ALL） and has good application prospects. Immunotherapy， including chimeric antigen receptor T cell immunotherapy （CAR-T） and monoclonal antibodies， has shown great potential for application， and has been approved for marketing. This article summarizes the application of the above two therapies in the treatment of relapsed/ refractory B-ALL， and concludes that CAR-T is a kind of personalized immunotherapy， and the selection of ideal targets is an important part of its action. Currently， the ideal targets in clinical studies include CD19， CD22 and CD19/CD22. Monoclonal antibodies， including blinatumomab and inotuzumab ozogamicin， have shown superior therapeutic efficacy for relapsed/refractory B- ALL. Immunotherapy has shown superior therapeutic effects compared to conventional chemotherapy， expanding the selection of treatment options for relapsed/refractory B-ALL.

Mechanism of monoclonal antibody against interleukin IL-17A regulating autophagy and inflammation in gout / 中国生物制品学杂志

@#Objective To investigate the mechanism of anti-IL-17A monoclonal antibody(secukinumab) regulating autophagy and inflammation in gout.Methods The peripheral venous blood samples from 57 patients with acute gout(AG),57patients with intermittent gout(IG) and 82 healthy volunteers were collected and measured for the mRNA transcription levels of autophagy-related genes(ATGs) ATG4B,ATG7, A TG16L1,Beclin-1 and LC3B by RT-qPCR.The model of AG inflammation was established by adding monosodium urate(MSU) crystals into the peripheral venous blood samples of healthy volunteers,and the transcription and protein expression of IL-1β were detected by RT-qPCR and ELISA at 0,1,2,4,6 and8 h and different concentrations(0,100,200 and 400 μmol/L) of secukinumab.The peripheral blood samples of healthy volunteers were divided into control(without MSU treatment),MSU(100 μg/mL),MSU+colchicine(100 μg/mL+30 μg/mL) and MSU+secukinumab(100 μg/mL+400 μmol/L) groups,which were detected for the mRNA transcription and protein expression of IL-1 β and ATGs by RT-qPCR and Western blot,and for the expression of IL-1β,IL-12 and IL-35 by ELISA.Results The mRNA expression levels of ATG4B, Beclin-1 and LC3B in AG,IG and healthy control groups were significantly different(F=3.896,11.78 and 3.856,respectively,each P <0.05),among which the mRNA levels in AG were lower than those in IG and HC groups(t=2.692,3.234,2.231 and 2.085,4.795,2.748,respectively,each P <0.05);the expression levels of ATG16L1 mRNA were significantly different in the three groups(F=7.949,P <0.001),and was significantly lower in AG group than HC group(t=3.860,P <0.001).In AG inflammation model,the mRNA and protein expression of IL-1 β reached their peak in 2—4 h,and the anti-inflammation effect of secukinumab was the strongest at the concentration of 400 μmol/L.Compared with MSU group,the mRNA levels of ATG16L1 and LC3B(t=2.343 and 2.916,respectively,each P <0.05) as well as the expression levels of ATG4B,ATG7,Beclin-1,ATG16L1 and LC3B-Ⅱ proteins(t=28.84,11.6,8.402,4.124 and 2.458,respectively,each P <0.05) in MSU+secukinumab group decreased significantly.The expression levels of IL-12 and IL-35 in the control,MSU,MSU+colchicine and MSU+secukinumab groups showed significant difference(F=7.009 and 6.518,respectively,each P <0.01).Compared with MSU group,the expression level of IL-12 significantly decreased(t=2.604,P <0.05)in MSU+secukinumab group,and the expression level of IL-35 also decreased,while with no significant difference(t=1.928,P> 0.05).Conclusion Secukinumab can regulate the mRNA and protein expression of ATGs,reduce the levels of pro-inflammatory cytokines,and inhibit gout inflammation,which provides a reference for the treatment of gout.

Clinical application and progression of monoclonal antibodies targeting HER2 extracellular domain Ⅳ in breast cancer / 中国药房

Human epidermal growth factor receptor 2 （HER2）-positive breast cancer is aggressive and prone to metastasis，and the applications of HER2 agents have improved the prognosis of patients with HER2-positive breast cancer. Among the marketed HER2 agents，macromolecular monoclonal antibodies that target the extracellular domain Ⅳ of HER2 were the cornerstone drugs of HER2-positive breast cancer，including trastuzumab，inetetamab，and margetuximab. Trastuzumab is available for the full-line treatment of breast cancer with sufficient proof of evidence-based medicine，sufficient practical experience and controllable safety. Inetetamab and trastuzumab have similar efficacy and controllable safety in HER2-positive metastatic breast cancer and neoadjuvant/ adjuvant therapy. Margetuximab focuses on patients carrying the CD16A-158F allele，and is an option of posterior line treatment for advanced breast cancer. It is necessary to select the most suitable drugs clinically according to the specific condition of the patient.

Regressão da polipose nasal induzida pelo dupilumabe / Regression of dupilumab-induced nasal polyps

Relato de caso de paciente com rinossinusite crônica com polipose nasal em tratamento com dupilumabe. São descritos os aspectos clínicos e o impacto na qualidade da vida do paciente. Imagens tomográficas evidenciam a melhora do processo inflamatório e a regressão dos pólipos nasais.

We report the case of a patient with chronic rhinosinusitis with nasal polyps treated with dupilumab. The clinical features and impact on the patient's quality of life are described. Computed tomography shows improvement of the inflammatory process and regression of the nasal polyps.

Perfil de pacientes com urticária crônica espontânea submetidos ao tratamento com omalizumabe em Chapecó, SC / Profile of patients with chronic spontaneous urticaria treated with omalizumab in Chapecó, south of Brazil

Introdução: A urticária crônica espontânea é caracterizada por lesões máculo-papulares eritematosas, associadas a prurido e angioedema, que não possui estímulo externo reconhecido e de difícil controle. A primeira e a segunda linha terapêutica, disponibilizadas pelo Sistema Único de Saúde, não apresentam resultados significativos, os quais se tornam refratários. O omalizumabe, considerado terceira linha terapêutica e que não é amplamente disponibilizado pelo Sistema Único de Saúde, pode apresentar resultado significativo na interrupção dos sintomas da doença. Objetivo: O presente estudo tem como objetivo avaliar pacientes com urticária crônica espontânea que usaram ou estão em uso de omalizumabe. Métodos: Trata-se de um estudo observacional transversal do tipo série de casos, cuja análise foi feita através dos prontuários, com população de 34 pacientes com urticária crônica espontânea submetidos ao tratamento com omalizumabe no Instituto de Olhos de Santa Catarina (IOSC). Resultados: Constatou-se no estudo que a maioria dos pacientes com urticária crônica espontânea em uso de omalizumabe é constituída do sexo feminino (76,5%) e idade média de 41 anos. A doença mais associada à urticária crônica espontânea foi depressão (38,2%). O sucesso do tratamento com omalizumabe é medido pelo questionário UAS7 (Urticaria Activity Score), o qual, segundo os dados dos prontuários, todos os pacientes apresentavam resultado maior que 35 pontos antes do uso da medicação, e 32 conseguiram alcançar um índice de 0 após o uso do omalizumabe, variando apenas no tempo de tratamento. Conclusão: A urticária crônica espontânea é uma doença que não tem cura e possui alta refratariedade, mas pode ter seus sintomas reduzidos, principalmente com o uso do omalizumabe, que se mostrou eficiente nos casos analisados.

Introduction: Chronic spontaneous urticaria is a disease characterized by erythematous maculopapular eruption, associated with itching and angioedema, that has no recognized external stimulus and is difficult to control. First- and second-line treatments, available through the Brazilian Unified Health System, do not yield meaningful results, and patients become refractory. Omalizumab, considered a third-line treatment and not widely available through the Brazilian Unified Health System, may yield meaningful results in halting disease symptoms. Objective: To evaluate patients with chronic spontaneous urticaria who have used or are using omalizumab. Methods: We conducted a cross-sectional case series observational study with a review of the medical records of 34 patients with chronic spontaneous urticaria treated with omalizumab at the Eye Institute of Santa Catarina, south of Brazil. Results: Most patients with chronic spontaneous urticaria receiving omalizumab were female (76.5%) with a mean age of 41 years. The disease most commonly associated with chronic spontaneous urticaria was depression (38.2%). Omalizumab treatment success was measured with the Urticaria Activity Score (UAS7). Based on data extracted from the medical records, all 34 patients had a score greater than 35 before treatment. After receiving omalizumab, 32 patients managed to reach a score of 0, differing only in the duration of treatment. Conclusion: Chronic spontaneous urticaria is an incurable, highly refractory disease, but its symptoms can be reduced mainly with the use of omalizumab, which proved to be effective in the cases analyzed here.

Eficacia del nimotuzumab según índices inflamatorios en pacientes con cáncer de pulmón no microcítico avanzado

Introducción: La respuesta a las terapias en el cáncer de pulmón avanzado pudiera estar relacionada con determinados factores pronósticos como los índices inflamatorios. Objetivo: Evaluar la eficacia del anticuerpo monoclonal humanizado nimotuzumab en pacientes portadores de cáncer de pulmón no microcítico avanzado según índices inflamatorios. Método: Se realizó un estudio de evaluación longitudinal retrospectivo, en un universo de 498 pacientes mayores de 18 años, con diagnóstico citohistológico de cáncer de pulmón de células no pequeñas, en estadios avanzados, después de la primera línea de terapia oncológica, incluidos en ensayos clínicos multicéntricos promovidos por el Centro de Inmunología Molecular desde 2002 a 2018. Se aplicó la estadística descriptiva, se utilizó el software x-tile 3.6.1 para el test de Kaplan Meier; se consideraron diferencias significativas cuando p< 0,05. Resultados: En los pacientes analizados el nimotuzumab mostró beneficio terapéutico en el grupo de pacientes no progresores a la primera línea de tratamiento con quimioterapia o quimiorradioterapia, cuando tenían menor índice de neutrófilos/linfocitos (p= 0,017 y p= 0,027) y menor índice de plaquetas/linfocitos (p= 0,030 y p= 0,009). Conclusión: La selección de un paciente con menor índice inflamatorio beneficia la eficacia del tratamiento con el AcM humanizado nimotuzumab en el cáncer de pulmón avanzado no microcítico, la que se convierte en una herramienta predictiva de la respuesta al tratamiento.

Introduction: The response to therapies in advanced lung cancer could be related to certain prognostic factors such as inflammatory indices. Objective: To evaluate the efficacy of the humanized monoclonal antibody nimotuzumab in patients with advanced non-small cell lung cancer according to inflammatory indices. Method: A retrospective longitudinal evaluation study was carried out in a universe of 498 patients older than 18 years, with a cytohistological diagnosis of non-small cell lung cancer, in advanced stages, after the first line of oncological therapy, including in multicenter clinical trials promoted by the Center for Molecular Immunology from 2002 to 2018. Descriptive statistics were applied, the x-tile 3.6.1 software was used for the Kaplan Meier test, significant differences were considered when p< 0,05. Results: In the patients analyzed, nimotuzumab showed therapeutic benefit in the group of patients who did not progress to the first line of treatment with chemotherapy or chemoradiotherapy, when they had a lower neutrophil-lymphocyte index (p= 0,017 and p= 0,027) and a lower platelet-lymphocyte index (p= 0,030 and p= 0,009). Conclusion: Selecting a patient with a lower inflammatory index benefits the efficacy of treatment with the humanized mAb nimotuzumab in advanced non-small cell lung cancer, which becomes a predictive tool for response to treatment.

Use of monoclonal antibodies in cancer immunotherapy: types and mechanisms of action / Uso de anticuerpos monoclonales en la inmunoterapia del cáncer: tipos y mecanismos de acción

Abstract Immunotherapy is one of the most innovative treatments in the current field of oncology and consists of stimulating the immune system to eliminate tumoral cells. Monoclonal antibodies (mAbs) are glycoproteins secreted by B-cells capable of recognizing and neutralizing foreign organisms or antigens. Structurally, they are composed of two heavy and two light chains. The generation of therapeutic mAbs is one of the most developed and fastest-growing areas of the biotechnological and pharmaceutical industries and is an important adjunct to cancer therapy. Several antibodies have been approved for human administration and can be mouse-derived, chimeric, humanized, or fully human. mAbs main mechanism of action includes the lysis of the tumoral cells through inducing apoptosis, phagocytosis, complement activation, or signaling inhibition.

Resumen La inmunoterapia es un tratamiento innovador para la oncología actual, que consiste en la estimulación del sistema inmunitario para la eliminación de las células tumorales. Los anticuerpos monoclonales (mAbs) son glicoproteínas secretadas por los linfocitos B, capaces de reconocer y neutralizar organismos extraños o antígenos. Estructuralmente se componen de dos cadenas pesadas y dos cadenas ligeras. La generación de mAbs terapéuticos es una de las áreas de mayor crecimiento en la industria biotecnológica y farmacéutica y representa un complemento importante en la terapia del cáncer. Existen diversos mAbs que han sido aprobados para su administración en humanos, y pueden ser derivados de ratón, quiméricos, humanizados o completamente humanos. Los mecanismos de acción consisten principalmente en la lisis de las células tumorales a través de la inducción de la apoptosis, fagocitosis, activación del complemento o inhibición de la señalización celular.

Multiple Myeloma (Part 1) - Update on Epidemiology, Diagnostic Criteria, Systemic Treatment and Prognosis / Mieloma múltiplo (Parte 1) - Atualização sobre epidemiología, critérios diagnósticos, tratamento sistêmico e prognóstico

Abstract Multiple myeloma (MM) is a hematological malignancy characterized by unregulated and clonal proliferation of plasma cells in the bone marrow; these cells produce and secrete an anomalous monoclonal immunoglobulin, or a fragment of this, called M protein. The clinical manifestations of MM result from the proliferation of these plasmocytes, the excessive production of monoclonal immunoglobulin and the suppression of normal humoral immunity, leading to hypercalcemia, bone destruction, renal failure, suppression of hematopoiesis and humoral immunity, increasing the risk for the development of infections. The increase in life expectancy of the world population led to a concomitant increase in the prevalence of MM, a pathology that usually affects the elderly population. The aim of this review is to update the reader on epidemiology, diagnostic criteria, differential diagnosis with other monoclonal gam-mopathies, systemic treatment and prognosis of MM.

Resumo O mieloma múltiplo (MM) constitui neoplasia maligna de origem hematológica caracterizada pela proliferação desregulada e clonal de plasmócitos na medula óssea; estas células produzem e secretam imunoglobulina monoclonal anômala, ou um fragmento desta, denominado proteína M. As manifestações clínicas do MM decorrem da proliferação destes plasmócitos, da produção excessiva de imunoglobulina monoclonal e da supressão da imunidade humoral normal, levando à hipercalcemia, destruição óssea, insuficiência renal, supressão da hematopoiese e da imunidade humoral,aumentandooriscoparaodesenvolvimento de infecções. O aumento na expectativa de vida da população mundial levou a concomitante incremento na prevalência do MM, patologia que habitualmente acomete a população idosa. O objetivo desta revisão é atualizar o leitor sobre a epidemiologia, critérios diagnósticos, diagnóstico diferencial com outras gamopatias monoclonais, tratamento sistêmico e prognóstico do MM.

Current strategies and perspectives for active and passive immunization against Respiratory Syncytial Virus in childhood

Abstract Objectives: Despite the global impact of the Respiratory Syncytial Virus (RSV) infection in children, only one monoclonal antibody (Palivizumab) has been approved for clinical use. However, advances in the knowledge of RSV immunology may enable the development of safe and effective new vaccines and monoclonal antibodies in a few years. The purpose of this review is to summarize available data on approved and developing passive and active immunizations against RSV in childhood and pregnancy. Data source: A non-systematic review of RSV immunoprophylaxis in childhood and pregnancy was carried out in PubMed, path.org and clinical trial registries, without language restrictions, up to September 2022. Data synthesis: Three monoclonal antibodies and 17 active immunization candidates are under development in phase 1 to 3 clinical studies. Regarding the first group, Nirsevimab is a monoclonal antibody with a prolonged half-life whose approval for clinical use is expected in the next months. Among the vaccines under development, six techniques are being used: protein subunit, viral particles, live attenuated virus, recombinant viral vector, chimeric, and mRNA. The first two approaches are being tested primarily in pregnancy, while the others are being developed for the pediatric population. Conclusion: The approval of extended half-life monoclonal antibodies is the next expected advance in RSV prevention, although the costs may be a barrier to the implementation. Regarding active immunizations, maternal and infant vaccination are complementary strategies and there are many promising candidates in clinical studies using different platforms.

Rituximab, a Safer Option for Rheumatoid Arthritis: A Comparison of the Reported Adverse Events of Approved Monoclonal Antibodies

Monoclonal antibodies (mAbs), which are commonly used to treat rheumatoid arthritis (RA), have been linked to a variety of adverse events (AEs). The objective of the study was to compare the safety profiles of six FDA approved mAbs (sarilumab, tocilizumab, adalimumab, golimumab, infliximab, and rituximab) marketed for the treatment of RA. A systematic review of the literature was conducted using the databases PubMed, Cochrane Library, and Science Direct. The manuscript comprised a total of 23 clinical studies. The percentage of patients who had AEs was calculated and presented using box-whisker and forest plots. Infections and infestations were found to be the most common AEs in RA patients treated with mAbs. Raised alanine aminotransferase (ALT), aspartate aminotransferase (AST), upper respiratory tract infection (URTI), and nasopharyngitis were frequently reported. The most common AEs were reported with adalimumab. The highest percentage of patients reporting AEs was associated with golimumab (52%), while rituximab had the fewest AEs (4.9%). In conclusion, rituximab appears to be a safer treatment option for RA as it is found to be associated with a lower risk of AEs, particularly respiratory infections.

Beneath the surface: a case report of metastatic iridociliary ring melanoma treated with pembrolizumab / Abaixo da superfície: relato de caso de melanoma metastático iridociliar em anel tratado com pembrolizumabe

ABSTRACT Iridociliary ring melanoma is an uncommon type of uveal melanoma. Clinical manifestation varies from asymptomatic cases to masquerade syndromes mimicking refractory glaucoma. Treatment options include radiotherapy and enucleation. Management of metastatic uveal melanoma remains discouraging. Novel therapies using immune checkpoint inhibitors are currently under study. We present a case of a 54-year-old Hispanic woman with progressive vision loss due to metastatic ring melanoma with anterior chamber seeding treated with pembrolizumab.

RESUMO O melanoma iridociliar em anel é um tipo incomum de melanoma uveal. As manifestações clínicas variam desde casos assintomáticos até síndromes mascaradas que mimetizam um glaucoma refratário. As opções de tratamento incluem radioterapia e enucleação. O manejo do melanoma uveal metastático continua desanimador. Novas terapias usando inibidores de checkpoint imunológico estão atualmente em estudo. Apresentamos o caso de uma mulher hispânica de 54 anos com perda progressiva da visão por um melanoma metastático em anel, com semeadura de câmara anterior, tratada com pembrolizumabe.

Determining reference ranges for immunological cells of healthy indigenous individuals from a region in Brazil

ABSTRACT Objective The establishment of reference values for a subset of leukocytes is common in clinical practice, and ethnic variations are strongly associated with disease development. In Brazil, indigenous people are vulnerable to infections, and few studies have described the health and disease conditions of this population. This study aimed to provide reference values for immunological cell subsets in indigenous Brazilians living in the state of Mato Grosso do Sul. Methods Flow cytometry and 4-color combinations of monoclonal antibodies were used to characterize cells. A total of 115 healthy adults, mostly females (72%), were included in the study. The results are presented as mean and median (2.5%-97.5% percentiles) for T and B lymphocytes, CD4+ T cells, CD8+ T cells, Natural Killer cells, monocytes, and dendritic cells, providing an average immunological profile for the population in question. Results The relative medians of CD3+, CD4+, and CD8+ T cells were significantly higher in women than in men in a healthy indigenous population. Conclusion To our knowledge, cell reference data from indigenous Brazilians are unknown in the literature. The immune cell results presented in this pioneering study will contribute to the clinical and laboratory evaluation of the Brazilian indigenous population, especially given the important differences when compared with other Brazilian ethnic groups.

Migraine treatment with biological therapies. The state of the art / Tratamento da enxaqueca com terapias biológicas. O Estado da arte

Migraine is a highly prevalent and debilitating neurological disorder. Most patients do not receive a correct diagnosis and effective treatments. Apart of the few specialists and tertiary centers worldwide, the treatment of migraine is usually symptomatic and prevention, as well as treatments of the underlying mechanisms, are not aimed. It results in frustration and substantial burden. The last few years witnessed the releasing of specific biological therapies, mostly addressing one of the peptides involved in migraine pathophysiology, the calcitonin gene-related peptide (CGRP). Either the small molecules as well as the monoclonal antibodies against CGRP or its canonical receptor have been launched in markets across the globe and represent interesting options for the treatment of migraine. Onabotulinumtoxin A has also been proposed for chronic migraine as well, but not for episodic migraine, based on its unique ability to inhibit the SNARE complex formation and the release of numerous potential mediators of migraine. However, despite the favorable figures on efficacy and tolerability of these compounds, the regulations, and particulars of different countries, regarding the structures and reimbursement of medical care, demonstrated different adhesion profiles of chosen populations to receive these emerging weapons against migraine-imposed suffering. This review addresses the use and characteristics of biological therapies used in migraine treatment.

A enxaqueca é um distúrbio neurológico altamente prevalente e debilitante. A maioria dos pacientes não recebe um diagnóstico correto e tratamentos eficazes. Com exceção dos poucos especialistas e centros terciários em todo o mundo, o tratamento da enxaqueca é geralmente sintomático e a prevenção, bem como o tratamento dos mecanismos subjacentes, não são direcionados. Isso resulta em frustração e fardo substancial. Os últimos anos testemunharam o lançamento de terapias biológicas específicas, abordando principalmente um dos peptídeos envolvidos na fisiopatologia da enxaqueca, o peptídeo relacionado ao gene da calcitonina (CGRP). Tanto as pequenas moléculas como os anticorpos monoclonais contra CGRP ou o seu receptor canônico foram lançados em mercados em todo o mundo e representam opções interessantes para o tratamento da enxaqueca. A onabotulinumtoxina A também foi proposta para enxaqueca crônica, mas não para enxaqueca episódica, com base em sua capacidade única de inibir a formação do complexo SNARE e a liberação de numerosos mediadores potenciais da enxaqueca. No entanto, apesar dos números favoráveis ​​sobre a eficácia e tolerabilidade destes compostos, os regulamentos e particularidades de diferentes países, no que diz respeito às estruturas e reembolso dos cuidados médicos, demonstraram diferentes perfis de adesão das populações escolhidas para receber estas armas emergentes contra o sofrimento imposto pela enxaqueca. Esta revisão aborda o uso e as características das terapias biológicas utilizadas no tratamento da enxaqueca.

Evaluation of the use of CGRP monoclonal antibodies (mAbs) in migraine prophylaxis in a private clinic / Avaliação do uso de anticorpos monoclonais (mAbs) CGRP na profilaxia de enxaqueca em clínica privada

Introduction: Migraine is considered the second most prevalent neurological disorder in the population and highly disabling. Objective: The aim of this study is to evaluate the use of calcitonin gene-related peptide (CGRP) monoclonal antibodies in migraine prophylaxis, with emphasis on therapeutic response, adverse effects, and impacts on quality of life. Method; A quantitative, retrospective, and descriptive study was carried out, through the analysis of medical records and telephone interviews with patients seen at the Serviço de Neurologia e Neurocirurgia, in the city of Passo Fundo, RGS, Brazil, currently or previously having used at least one dose of the medication. Conclusion: Thus, it is understood that CGRP monoclonal antibodies are able to reduce monthly headache days, reduce pain intensity and promote improvement in work capacity. Therefore, they can be considered effective, safe and well-adhered medications for migraine prophylaxis.

Introdução: A enxaqueca é considerada o segundo distúrbio neurológico mais prevalente na população e altamente incapacitante. Objetivo: O objetivo deste estudo é avaliar o uso de anticorpos monoclonais do peptídeo relacionado ao gene da calcitonina (CGRP) na profilaxia da enxaqueca, com ênfase na resposta terapêutica, efeitos adversos e impactos na qualidade de vida. Método; Foi realizado um estudo quantitativo, retrospectivo e descritivo, por meio de análise de prontuários e entrevistas telefônicas com pacientes atendidos no Serviço de Neurologia e Neurocirurgia, na cidade de Passo Fundo, RGS, Brasil, que já usaram ou usaram pelo menos uma dose do medicamento. Conclusão: Assim, entende-se que os anticorpos monoclonais CGRP são capazes de reduzir os dias mensais de cefaleia, reduzir a intensidade da dor e promover melhora na capacidade de trabalho. Portanto, podem ser considerados medicamentos eficazes, seguros e de boa adesão para a profilaxia da enxaqueca.

Quantitation of certolizumab pegol by validated liquid chromatography methods

Abstract Certolizumab pegol (CZP) is a Fab' fragment of the humanized antibody with anti-TNF-α activity that is indicated as therapy for Crohn's disease and rheumatoid arthritis. Using a BioSep-SEC-S3000 column (300 x 4.6 mm i.d., 5 µm particle size), a size exclusion liquid chromatography (SEC) method was developed. Mobile phase A consisted of 100 mM monobasic sodium phosphate and 200 mM sodium chloride (pH 7.0), while mobile phase B was ethanol (95:5, v/v), and the analysis was performed using a diode array detector (DAD) set to 214 nm and a flow rate of 0.5 ml min-1. In addition, a reversed-phase liquid chromatography (RP-LC) method based on gradient elution was developed on a Zorbax 300 SB C18 column (150 mm x 4.6 mm i.d., 3.5 µm particle size) kept at 80 °C. Mobile phase A was 0.1% (v/v) TFA in ultrapure water, and mobile phase B was a mixture of propanol, acetonitrile, ultrapure water and TFA (70 + 20 + 9.9 + 0.1, v/v) operated at a flow rate of 1.0 ml min-1, and DAD was applied at 214 nm. CZP elution was achieved with retention times of 5.6 min and 9.0 min for SEC and RP-LC, respectively.