Imunização de camundongos LDLr-/- com peptídeo mimético da LDL eletronegativa: uma potencial estratégia terapêutica para a ateroscleros / Immunization of LDLr - / - mice with electronegative LDL mimetic peptides: a potential therapeutic strategy for atherosclerosis

Introdução: A aterosclerose é uma doença inflamatória crônica decorrente de alterações na parede das artérias de médio e grande calibre e associadas a diversos fatores de risco, dentre os quais destaca-se as hiperlipidemias, ou seja, o aumento plasmático das lipoproteínas, mas também outras comorbidades, como a Síndrome Metabólica. Entre as lipoproteínas, a lipoproteína de baixa densidade (LDL) é de grande relevância na aterosclerose. Diferentes espécies de LDL modificada (LDLm) são originadas através de lipólise, glicação e proteólise, além da oxidação, variando em densidade e eletronegatividade, sendo melhor denominada LDL eletronegativa [LDL (-)]. Considerando as diferenças conformacionais entre a estrutura da ApoB-100 da LDL nativa e da LDL (-), em um estudo inicial, nosso grupo desenvolveu um anticorpo monoclonal (2C7) a partir da imunização de camundongos Balb/c com a LDL (-) humana. Em uma etapa seguinte foi mapeado o epítopo reconhecido pelo anticorpo monoclonal anti-LDL (-) através de phage display. O peptídeo ligante do anticorpo monoclonal anti-LDL (-) foi nomeado p2C7. Esse peptídeo não representa regiões da sequência linear da ApoB-100 humana, mas microdomínios conformacionais de epítopos da ApoB-100 da LDL (-), tornando-os candidatos para a imunomodulação da aterogênese. Portanto, investigar a imunomodulação induzida pelos peptídeo p2C7 miméticos da LDL (-), por representar um epítopo imunodominante da LDL (-), poderá abrir novas perspectivas terapêuticas futuras para a imunomodulação da aterosclerose. Objetivo: Avaliar a imunomodulação promovida pelo p2C7 in vivo, utilizando camundongos C57BL/6 LDLr -/- e amostras de plasma humano. Adicionalmente, no estágio (BEPE) realizado no Instituto Karolinska (dezembro de 2019 a março de 2021), investigou-se o imunometabolismo como mediador nas doenças cardiovasculares. Na parte II-A, estão descritos os resultados do estudo inicialmente proposto. Na parte II-B, apresenta-se os resultados que foram desenvolvidos posteriormente, com ampliação do escopo do projeto, abordando-se a inflamação vascular envolvida no aneurisma de aorta abdominal através de ferramentas de bioinformática. Na parte II-C, são apresentados os resultados do estudo do envolvimento da enzima indolamina 2,3 dioxigenase (IDO) na esteatohepatite não-alcoólica (NASH) e aterosclerose em camundongos ApoE-/- and ApoE/IDO/double-knockout. Metodologia: Foi avaliada a presença de anticorpos anti-p2C7 em amostras de plasma humano de indivíduos com ou sem síndrome metabólica. Realizamos a determinação de TNF circulante nas mesmas amostras e prosseguimos com regressões lineares associando os parâmetros inflamatórios com os níveis de anticorpos anti-p2C7. Camundongos C57BL/6 LDLr -/- foram imunizados com p2C7 e os adjuvantes Alum ou Montanide ISA 720, analisando-se os títulos de anticorpos contra p2C7 e LDL (-), a produção de citocinas (IL-10, IL-4, IL-2, IL-6, IFNγ, IL-17, TNFα) e células secretoras de anticorpos. Camundongos C57BL/6 LDLr -/- foram tolerizados contra os peptídeos mimotopos, com injeções intravenosas (veia caudal) e desafiados com a imunização contendo LDL (-) + Alum. Avaliou-se os títulos de anticorpos contra p2C7 e LDL (-) e a produção de citocinas (TNF-α, IFNγ, IL-12, IL-6, IL-10 e MCP-1). Os camundongos foram mantidos em dieta hipercolesterolêmica por 3 meses para formação da placa aterosclerótica. Após este período, os camundongos foram eutanasiados, avaliando-se a formação de placa aterosclerótica na artéria abdominal e arco aórtico, assim como a produção de citocinas (TNF-α, IFNγ, IL-12, IL-6, IL-10 e MCP-1). Camundongos C57BL/6 LDLr -/- foram imunizados com OVA-p2C7 e, após dieta hipercolesterolêmica de 3 meses para formação de placa aterosclerótica, foram avaliados os parâmetros inflamatórios e avaliada a captação de 18F-FDG no arco aórtico através de PET/CT. Resultados: A imunização com o p2C7 (livre) não foi capaz de induzir resposta humoral, não se observando títulos detectáveis de anticorpos reativos à p2C7 ou LDL (-) em nenhum camundongo imunizado, assim como não foram detectadas células secretoras de anticorpos específicos para a LDL (-). O grupo imunizado com Alum ou Montanide + p2C7 teve aumento significativo na produção de TNF- quando comparado com os demais grupos. O protocolo de tolerização foi realizado com sucesso, visto que os camundongos tolerizados apresentaram títulos de anticorpos inferiores aos controles para o epítopo utilizado. Apenas os camundongos tolerizados com o p2C7 apresentaram aumento significativo na produção de IL-6, IL-12, IL-10, TNF-α, IFNγ e MCP 1 após dieta hipercolesterolêmica. A imunização ativa com OVA-p2C7 foi capaz de reduzir a produção de TNF induzida pela dieta hipercolesterolêmica, assim como reduzir a captação de 18F-FDG. Conclusão: o epítopo p2C7 é altamente expresso na LDL (-) de pacientes com maior risco cardiovascular. Além disso, a imunização ativa com p2C7 também se mostra uma ferramenta promissora para prevenir e regular a inflamação causada pela LDL (-) no curso da aterosclerose

Introduction: Atherosclerosis is a chronic inflammatory disease resulting from changes in the wall of medium and large-caliber arteries and associated with several risk factors, among which hyperlipidemias stand out, ie, the increase in plasma lipoproteins, but also other comorbidities, such as Metabolic Syndrome. Among the lipoproteins, low-density lipoprotein (LDL) is of great relevance in atherosclerosis. Different isoforms of modified LDL (LDLm) are originated through lipolysis, glycation and proteolysis, in addition to oxidation, varying in density and electronegativity, being better called electronegative LDL [LDL (-)]. Considering the conformational differences between the ApoB-100 structure of native LDL and LDL (-), in an initial study, our group developed a monoclonal antibody (2C7) from the immunization of Balb/c mice with human LDL (-). In a next step, the epitope recognized by the anti-LDL monoclonal antibody (-) was mapped using phage display. The binding peptide of anti-LDL monoclonal antibodies (-) was named p2C7. This peptide does not represent linear sequence regions of human ApoB-100, but conformational microdomains of LDL (-) ApoB-100 epitopes, making them candidates for the immunomodulation of atherogenesis. Therefore, investigating the immunomodulation induced by p2C7 peptide mimetics of LDL (-) as it represents an immunodominant epitope of LDL (-) could open new future therapeutic perspectives for the immunomodulation of atherosclerosis. Objective: To evaluate the immunomodulation promoted by p2C7 in vivo, using C57BL/6 LDLr -/- mice, and human plasma samples. In addition, in the internship (BEPE), held at the Karolinska Institute (December 2019 to March 2021), immunometabolism as a mediator of Cardiovascular Diseases was studied. In part II-A, the results of the initially proposed study are described. In part II-B, the results that were developed later are presented, expanding the scope of the project, approaching the vascular inflammation involved in the abdominal aortic aneurysm through bioinformatics tools. In part II-C, the results of the study of the involvement of the enzyme indoleamine 2,3 dioxygenase (IDO) in non-alcoholic steatohepatitis (NASH) and atherosclerosis in ApoE-/- and ApoE/IDO/double mice are presented -knockout. Methodology: The presence of anti-p2C7 antibodies in human plasma samples with or without Metabolic Syndrome was evaluated. We measured circulating TNF in the same samples and proceeded with linear regressions associating inflammatory parameters with levels of anti-p2C7 antibodies. C57BL/6 LDLr -/- mice were immunized with p2C7 and the adjuvants Alum or Montanide ISA 720, analyzing the antibody titers against p2C7 and LDL (-), the production of cytokines (IL-10, IL-4, IL -2, IL-6, IFNγ, IL-17, TNFα) and antibody-secreting cells. C57BL/6 LDLr -/- mice were tolerized against mimotope peptides with intravenous injections (caudal vein) and challenged with immunization containing LDL (-) + Alum. Antibody titers against p2C7 and LDL (-) and cytokine production (TNF-α, IFNγ, IL-12, IL-6, IL-10 and MCP-1) were evaluated. The mice were kept on a hypercholesterolemic diet for 3 months for atherosclerotic plaque formation. After this period, the mice were euthanized, evaluating the formation of atherosclerotic plaque in the abdominal artery and aortic arch, as well as the production of cytokines (TNF-α, IFNγ, IL-12, IL-6, IL-10 and MCP -1). C57BL/6 LDLr -/- mice were immunized with OVA-p2C7 and, after a 3-month hypercholesterolemic diet for atherosclerotic plaque formation, inflammatory parameters were evaluated and 18F-FDG uptake was evaluated by PET/CT. Results: Immunization with p2C7 (free) was not able to induce a humoral response, with no detectable titers of antibodies reactive to p2C7 or LDL (-) being observed in any immunized mouse, as well as no detectable antibody-secreting cells for the LDL (-). The group immunized with Alum or Montanide + p2C7 had a significant increase in TNF-α production when compared to the other groups. The tolerance protocol was successfully performed, as the tolerized mice had lower antibody titers than controls for the epitope used. Only mice tolerated with p2C7 showed a significant increase in the production of IL-6, IL-12, IL-10, TNF-α, IFNγ and MCP 1 after a hypercholesterolemic diet. Active immunization with OVA-p2C7 was able to reduce TNF production induced by the hypercholesterolemic diet, as well as to reduce 18F-FDG uptake. Conclusion: the p2C7 epitope is highly expressed in LDL (-) of patients with higher cardiovascular risk. Furthermore, active immunization with p2C7 is also a promising tool to prevent and regulate inflammation caused by LDL (-) in the course of atherosclerosis

Assistência Farmacêutica a Pacientes Oncológicos em Uso de Anticorpos Monoclonais em um Hospital de Referência do Oeste de Santa Catarina / Pharmaceutical Assistance to Oncological Patients Using Monoclonal Antibodies in a Reference Hospital in the west of Santa Catarina / Asistencia Farmacéutica a Pacientes Oncológicos que Utilizan Anticuerpos Monoclonales en un Hospital de Referencia en el Oeste de Santa Catarina

Introdução: A utilização dos anticorpos monoclonais vem sendo incorporada aos protocolos de tratamento para câncer, uma vez comprovada sua eficácia. Essa modalidade de terapia é onerosa, e sua aquisição ainda constitui um obstáculo para o paciente. Objetivo: Descrever a utilização de anticorpos monoclonais no que tange à forma de aquisição, regulação e judicialização, efeitos adversos e causas de interrupção da terapia. Método: Estudo descritivo com avaliação de pacientes (n=169) em tratamento para câncer, em um hospital público, no período de 1 de agosto de 2017 a 31 de julho de 2019. Resultados: A população estudada foi majoritariamente feminina (n=115). As principais neoplasias encontradas foram de mama (n=64, 36,16%), linfomas (n=53, 29,94%) e mieloma múltiplo de plasmócito/plasmocitoma (n=25, 14,12%). Os anticorpos monoclonais mais utilizados foram o trastuzumabe (n=65, 35,71%) e rituximabe (n=54, 29,67%). Foram observadas quatro formas de aquisição dos fármacos. As aquisições por meio do Sistema Único de Saúde (SUS) (n=103, 56,59%) e judicial (n=72, 39,56%) prevaleceram. A maioria dos pacientes não apresentou efeitos adversos à terapia (60,3%); mas, entre os que apresentaram, os principais efeitos foram vômitos e náuseas, astenia, diarreia, dor, neutropenia e mucosite. Efeitos adversos/toxicidade (n=15), falta de medicamento (n=11) e atraso na liberação (n=10) foram as causas mais comuns de interrupção do tratamento. Conclusão: Os anticorpos monoclonais são mais específicos e apresentam menores efeitos. Aos fármacos indisponíveis pelo SUS, a judicialização mostra-se como uma ferramenta importante

Introduction: The use of monoclonal antibodies has been incorporated into cancer treatment protocols, once their effectiveness has been proven. This type of therapy is costly and its acquisition is still an obstacle for the patient. Objective: To describe the use of monoclonal antibodies in the perspective of purchasing, regulation and judicialization, adverse effects and causes of therapy discontinuation. Method: Descriptive study evaluating patients (n=169) undergoing treatment for cancer in a public hospital, from August 1, 2017 to July 31, 2019. Results: The population investigated consisted mostly of females (n=115). The main neoplasms found were breast (n=64, 36.16%), lymphomas (n=53, 29.94%) and plasma cell/plasmacytoma multiple myeloma (n=25, 14.12%). The most used monoclonal antibodies were trastuzumab (n=65, 35.71%) and rituximab (n=54, 29.67%). Four forms of drug purchase were observed. The purchases through the National Health System (SUS) (n=103, 56.59%) and law-mandated (n=72, 39.56%) prevailed. Most patients had no therapy-related adverse effects (60.3%), but among those who did, the main effects were vomiting and nausea, asthenia, diarrhea, pain, neutropenia and mucositis. Adverse effects/toxicity (n=15), lack of medication (n=11) and delayed approval (n=10) were the most common causes of treatment discontinuation. Conclusion: Monoclonal antibodies are more specific and have lesser effects. For drugs unavailable at SUS, judicialization is an important tool

Introducción: El uso de anticuerpos monoclonales se ha incorporado a los protocolos de tratamiento del cáncer, una vez comprobada su eficacia. Este tipo de terapia es costosa y su adquisición sigue siendo un obstáculo para el paciente. Objetivo: Describir el uso de anticuerpos monoclonales en términos de adquisición, regulación y judicialización, efectos adversos y causas de interrupción de la terapia. Método: Estudio descriptivo que evaluó a pacientes (n=169) en tratamiento por cáncer, en un hospital público, desde el 1 de agosto de 2017 al 31 de julio de 2019. Resultados: La población estudiada fue mayoritariamente femenina (n=115). Las principales neoplasias encontradas fueron mama (n=64, 36,16%), linfomas (n=53, 29,94%) y mieloma múltiple de células plasmáticas/plasmocitomas (n=25, 14,16%). Los anticuerpos monoclonales más utilizados fueron trastuzumab (n=65, 35,71%) y rituximab (n=54, 29,67%). Se observaron cuatro formas de adquisición de fármacos. Predominaron las adquisiciones a través del Sistema Único de Salud (SUS) (n=103, 56,59%) y judiciales (n=72, 39,56%). La mayoría de los pacientes no presentaron efectos adversos a la terapia (60,3%), pero entre los que sí los tuvieron, los principales efectos fueron vómitos y náuseas, astenia, diarrea, dolor, neutropenia y mucositis. Los efectos adversos/toxicidad (n=15), la falta de medicación (n=11) y la liberación retardada (n=10) fueron las causas más frecuentes de interrupción del tratamiento. Conclusión: Los anticuerpos monoclonales son más específicos y tienen menos efectos. Para los medicamentos no disponibles en el SUS, la judicialización es una herramienta importante

Assistência Farmacêutica a Pacientes Oncológicos em Uso de Anticorpos Monoclonais em um Hospital de Referência do Oeste de Santa Catarina / Pharmaceutical Assistance to Oncological Patients Using Monoclonal Antibodies in a Reference Hospital in the west of Santa Catarina / Asistencia Farmacéutica a Pacientes Oncológicos que Utilizan Anticuerpos Monoclonales en un Hospital de Referencia en el Oeste de Santa Catarina

Introdução: A utilização dos anticorpos monoclonais vem sendo incorporada aos protocolos de tratamento para câncer, uma vez comprovada sua eficácia. Essa modalidade de terapia é onerosa, e sua aquisição ainda constitui um obstáculo para o paciente. Objetivo: Descrever a utilização de anticorpos monoclonais no que tange à forma de aquisição, regulação e judicialização, efeitos adversos e causas de interrupção da terapia. Método: Estudo descritivo com avaliação de pacientes (n=169) em tratamento para câncer, em um hospital público, no período de 1 de agosto de 2017 a 31 de julho de 2019. Resultados: A população estudada foi majoritariamente feminina (n=115). As principais neoplasias encontradas foram de mama (n=64, 36,16%), linfomas (n=53, 29,94%) e mieloma múltiplo de plasmócito/plasmocitoma (n=25, 14,12%). Os anticorpos monoclonais mais utilizados foram o trastuzumabe (n=65, 35,71%) e rituximabe (n=54, 29,67%). Foram observadas quatro formas de aquisição dos fármacos. As aquisições por meio do Sistema Único de Saúde (SUS) (n=103, 56,59%) e judicial (n=72, 39,56%) prevaleceram. A maioria dos pacientes não apresentou efeitos adversos à terapia (60,3%); mas, entre os que apresentaram, os principais efeitos foram vômitos e náuseas, astenia, diarreia, dor, neutropenia e mucosite. Efeitos adversos/toxicidade (n=15), falta de medicamento (n=11) e atraso na liberação (n=10) foram as causas mais comuns de interrupção do tratamento. Conclusão: Os anticorpos monoclonais são mais específicos e apresentam menores efeitos. Aos fármacos indisponíveis pelo SUS, a judicialização mostra-se como uma ferramenta importante

Introduction: The use of monoclonal antibodies has been incorporated into cancer treatment protocols, once their effectiveness has been proven. This type of therapy is costly and its acquisition is still an obstacle for the patient. Objective: To describe the use of monoclonal antibodies in the perspective of purchasing, regulation and judicialization, adverse effects and causes of therapy discontinuation. Method: Descriptive study evaluating patients (n=169) undergoing treatment for cancer in a public hospital, from August 1, 2017 to July 31, 2019. Results: The population investigated consisted mostly of females (n=115). The main neoplasms found were breast (n=64, 36.16%), lymphomas (n=53, 29.94%) and plasma cell/plasmacytoma multiple myeloma (n=25, 14.12%). The most used monoclonal antibodies were trastuzumab (n=65, 35.71%) and rituximab (n=54, 29.67%). Four forms of drug purchase were observed. The purchases through the National Health System (SUS) (n=103, 56.59%) and law-mandated (n=72, 39.56%) prevailed. Most patients had no therapy-related adverse effects (60.3%), but among those who did, the main effects were vomiting and nausea, asthenia, diarrhea, pain, neutropenia and mucositis. Adverse effects/toxicity (n=15), lack of medication (n=11) and delayed approval (n=10) were the most common causes of treatment discontinuation. Conclusion: Monoclonal antibodies are more specific and have lesser effects. For drugs unavailable at SUS, judicialization is an important tool

Introducción: El uso de anticuerpos monoclonales se ha incorporado a los protocolos de tratamiento del cáncer, una vez comprobada su eficacia. Este tipo de terapia es costosa y su adquisición sigue siendo un obstáculo para el paciente. Objetivo: Describir el uso de anticuerpos monoclonales en términos de adquisición, regulación y judicialización, efectos adversos y causas de interrupción de la terapia. Método: Estudio descriptivo que evaluó a pacientes (n=169) en tratamiento por cáncer, en un hospital público, desde el 1 de agosto de 2017 al 31 de julio de 2019. Resultados: La población estudiada fue mayoritariamente femenina (n=115). Las principales neoplasias encontradas fueron mama (n=64, 36,16%), linfomas (n=53, 29,94%) y mieloma múltiple de células plasmáticas/plasmocitomas (n=25, 14,16%). Los anticuerpos monoclonales más utilizados fueron trastuzumab (n=65, 35,71%) y rituximab (n=54, 29,67%). Se observaron cuatro formas de adquisición de fármacos. Predominaron las adquisiciones a través del Sistema Único de Salud (SUS) (n=103, 56,59%) y judiciales (n=72, 39,56%). La mayoría de los pacientes no presentaron efectos adversos a la terapia (60,3%), pero entre los que sí los tuvieron, los principales efectos fueron vómitos y náuseas, astenia, diarrea, dolor, neutropenia y mucositis. Los efectos adversos/toxicidad (n=15), la falta de medicación (n=11) y la liberación retardada (n=10) fueron las causas más frecuentes de interrupción del tratamiento. Conclusión: Los anticuerpos monoclonales son más específicos y tienen menos efectos. Para los medicamentos no disponibles en el SUS, la judicialización es una herramienta importante

Prevention and treatment of mucocutaneous adverse reactions associated with epidermal growth factor receptor inhibitors / 中华预防医学杂志

The epidermal growth factor receptor (EGFR) signaling is aberrantly overexpressed in many solid malignancies, making it an important target for anti-cancer biologic agents. Among them, epidermal growth factor receptor inhibitors (EGFRIs), which have been widely used in clinical practice, include anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors. A proportion of patients treated with EGFRIs develop specific, dose-dependent skin toxicity such as papulopustular rash, paronychia, xerosis and itch. These side effects can cause physical and psychosocial discomfort that may result in dose reduction, discontinuance, or replacement of the current EGFRIs treatment. Correct diagnosis and treatment of these skin and mucosal adverse effects associated with EGFRIs is of great significance for the tertiary prevention of malignant tumors. A review on EGFRI-related mucocutaneous adverse reactions is presented here, focusing on the pathogenesis, the various clinical manifestations, the strategies for prevention and treatment of these conditions.

Immune checkpoint inhibitors induced pituitary immune-related adverse events: diagnosis and management / 中华肿瘤杂志

Immune checkpoint inhibitors (ICIs) have been used in treating a wide variety of cancers, but they challenge clinicians with a series of special immune related adverse events (irAEs) resulting from activated immune system. Since June 2018, when the first programmed cell death 1 (PD-1) inhibitor, nivolumab, was approved by the National Medical Products Administration (NMPA), abundant experience has been accumulated in coping with irAEs from PD-1 and PD-1 ligand 1 (PD-L1) blockade therapies. In October 2021, the first CTLA-4 inhibitor, ipilimumab, which has a different spectrum of irAEs was also approved by NMPA. The discrepancy in clinical features of pituitary irAEs is obvious between these two types of ICIs. Pituitary irAEs include hypophysitis and hypopituitarism. In this review of latest literature, we have summarized the incidence, possible mechanisms, time of onset, clinical presentations, hormone test, pituitary imaging, treatment strategies and recovery patterns of pituitary irAEs. By referring to domestic and foreign clinical guidelines, we have proposed practical suggestions for screening, diagnosing and treating pituitary irAEs.

Efficacy and safety of secukinumab in Chinese patients with moderate-to-severe plaque psoriasis: a real-life cohort study / 中华医学杂志(英文版)

BACKGROUND@#There have been few real-life dose-comparing studies on the efficacy and safety of secukinumab in Chinese patients with plaque psoriasis. We conducted a real-life cohort study to investigate the efficacy and safety of secukinumab 150 and 300 mg in Chinese patients with moderate-to-severe plaque psoriasis.@*METHODS@#A total of 106 patients with moderate-to-severe plaque psoriasis were included in this study. Patients received either secukinumab 150 mg or secukinumab 300 mg according to patients' weights and severity of psoriasis. The treatment continued for at least 24 weeks. The efficacy was evaluated by improvement in the psoriasis area and severity index (PASI) scores. The safety was also analyzed.@*RESULTS@#Fifty-nine patients (55.7%) were treated with secukinumab 300 mg and 47 patients (44.3%) were treated with secukinumab 150 mg. After 12-week treatment, PASI75/90/100 responses were achieved in 100%, 97.8%, and 95.7% of patients, respectively, in secukinumab 150 mg group, and the efficacy was maintained to week 24. In secukinumab 300 mg group, PASI75/90/100 responses were achieved in 93.2%, 81.4%, and 76.3% of patients, respectively, at week 12. In this group, PASI75/90/100 responses reached 91.5%, 86.4%, and 79.9%, respectively, at week 24. Biologic-experienced patients had lower responses than biologic-naïve patients. Secukinumab 150 and 300 mg were well tolerated. Five patients discontinued treatment due to poor response, adverse event, or economic reasons.@*CONCLUSIONS@#This real-life study demonstrated that high PASI 90 and PASI 100 responses were achieved in Chinese psoriasis patients receiving secukinumab 150 or 300 mg. Biologic-naïve was associated with better clinical efficacy.

Efficacy and safety of secukinumab in patients with psoriatic arthritis: A meta-analysis of different dosing regimens

The appropriate dosing regimens of secukinumab for psoriatic arthritis (PsA) are not well defined. We performed a meta-analysis to evaluate the efficacy and safety of different dosing regimens of secukinumab in the treatment of PsA. A systematic search was conducted using major electronic databases to identify relevant randomized controlled trials (RCTs) comparing secukinumab 300 mg versus secukinumab 150 mg in patients with PsA. Meta-analysis was performed using Review Manager software (version 5.3). Six studies with a total of 1141 patients were included. At week 24, secukinumab 300 mg was associated with a higher American College of Rheumatology 20% response (ACR 20), ACR 50, PASI 75 response rate, and dactylitis resolution rate than secukinumab 150 mg, especially in the anti-TNF-IR subgroup. At week 52, secukinumab 300 mg was associated with a higher psoriasis area and severity index (PASI) 75 and PASI 90 response rate than secukinumab 150 mg. There was no significant difference between secukinumab 300 mg and secukinumab 150 mg in the risk of any adverse events (AEs) and serious AEs at either week 24 or week 52. Secukinumab 300 mg was significantly more effective than 150 mg, especially for patients with PsA who have failed TNF therapy, and it was well tolerated.

Uso de fármacos anticorpos monoclonais, imunomoduladores e anti-inflamatórios no tratamento da infecção por COVID-19 / Use of monoclonal antibodies, immunomodulators, and anti-inflammatory drugs in the treatment of COVID-19

O objetivo deste estudo foi realizar o levantamento bibliográfico de artigos científicos e ensaios clínicos sobre a utilização de anticorpos monoclonais, imunomoduladores e anti-inflamatórios como possíveis alternativas terapêuticas para uso em pacientes com COVID-19, com ênfase nos mecanismos de ação e resultados de ensaios clínicos. Foram analisados artigos obtidos na base de dados MEDLINE® e ensaios clínicos disponíveis no site ClinicalTrials no período de 6 de abril a 6 de maio de 2020. Os ensaios realizados com os fármacos apresentados nesta revisão bibliográfica sugerem a viabilidade de uso de algumas dessas drogas como alternativas para tratamento da COVID-19. No entanto, observou-se que, em função do número reduzido de participantes dos estudos disponíveis, é indispensável a continuidade de pesquisas e dos ensaios clínicos com esses medicamentos, para estimar a eficácia dessas drogas no tratamento do SARS-CoV-2, contra o qual ainda não há terapia específica

The objective of this study was to carry out a bibliographic survey of scientific articles and current clinical trials on the use of monoclonal antibodies, immunomodulators, and anti-inflammatories as possible therapeutic alternatives for use in patients with COVID-19, highlighting their mechanisms of action and results of clinical trials. Articles from the MEDLINE® database and clinical trials available on the ClinicalTrials website were analyzedThe tests performed with the drugs presented in this bibliographic review suggest the feasibility of using some of these drugs as treatment alternatives for COVID-19. However, it was observed that the small samples evaluated in these tests make it imperative to proceed with research and clinical trials with these drugs to provide greater evidence of the effectiveness of these drugs in the treatment of the disease caused by SARS-CoV-2, for which there is no specific therapy so far.

Abordagem da conjuntivite em paciente com dermatite atópica em uso de dupilumabe / Management of conjunctivitis in patients with atopic dermatitis using dupilumab

O dupilumabe foi aprovado para o tratamento de dermatite atópica moderada a grave em adultos e adolescentes no Brasil. Ensaios clínicos e estudos de vida real mostraram alta eficácia e segurança deste imunobiológico, porém a frequência de conjuntivite no grupo de pacientes com dermatite atópica tratado com esse medicamento foi mais alta do que no grupo controle. A conjuntivite é mais frequente em pacientes com dermatite atópica do que na população geral, e foi o efeito adverso mais frequente nos pacientes com dermatite atópica em uso do dupilumabe. A maioria dos casos apresentou quadro leve, sem necessidade de suspender a medicação. Apresentamos uma sugestão de algoritmo para a abordagem da conjuntivite nos pacientes em uso do dupilumabe para tratamento da dermatite atópica.

Dupilumab has been approved for the treatment of moderate to severe atopic dermatitis in adults and adolescents in Brazil. Clinical trials and real-life studies have demonstrated the high efficacy and safety of this immunobiological agent, but the frequency of conjunctivitis in the group of patients treated with this drug for atopic dermatitis has been higher than that in the control group. Conjunctivitis is more common in patients with atopic dermatitis than in the general population, and it has been reported as the most common adverse effect in patients with atopic dermatitis using dupilumab. Most cases are of mild severity, without the need to discontinue medication. We suggest an algorithm for the management of conjunctivitis in patients treated with dupilumab for atopic dermatitis.

Efectos adversos inmunomediados por inhibidores de PD-1 / PD-1 inhibitors immune-mediated side effects

Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)

Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)

Consenso sobre riesgo de complicaciones infecciosas en pacientes usuarios de medicamentos biológicos seleccionados. Parte I / Consensus of infectious complications in patients treated with selected biological therapies: first Part

Resumen La incorporación de terapias biológicas ha significado un gran avance en el manejo de diversas patologías de origen autoinmune, neoplásico u otros. Si bien su uso ha implicado mejoras significativas en el pronóstico de estas enfermedades, no está exento de complicaciones, entre estas, las infecciosas. El objetivo de este consenso fue evaluar el perfil de seguridad, desde la mirada infectológica, de las terapias biológicas de uso más frecuente y dar recomendaciones para la prevención de infecciones en pacientes tratados con ellas, basándose en la evidencia de mayor calidad disponible para los biológicos seleccionados. El consenso cuenta de dos manuscritos. Esta primera parte detalla los riesgos de desarrollar complicaciones infecciosas dependiendo del tipo de biológico utilizado para determinada patología. La revisión incluyó búsqueda amplia en MEDLINE y Epistemonikos de revisiones sistemáticas y meta-análisis de estudios clínicos controlados y caso/control que examinaban infecciones posteriores al tratamiento con anti-TNF alfa, anti-CD20, anti-CD52, CTLA4-Ig y anti-integrinas. Esta búsqueda se complementó con revisión de cohortes multicéntricas de usuarios de biológicos, del MMWR del CDC, Atlanta, E.U.A. y de registros nacionales y/o de sociedades científicas en la que se hiciera mención a complicaciones infecciosas derivadas del uso de biológicos.

The use of biological therapies has meant a great improvement in the management of several conditions like autoimmune, neoplastic or others diseases. Although its use has implied significant improvements in the prognosis of these diseases, it is not exempt from complications: infectious diseases as one of them. The objective of this consensus was to evaluate, from an infectious viewpoint, the safeness of the most frequently used biological therapies and give recommendations for the prevention of infections in patients treated with these drugs. These recommendations were based on the highest quality evidence available for the selected biologics. The consensus counts of two manuscripts. This first part details the risks of developing infectious complications depending on the type of biological used for a certain pathology. This evaluation included a broad search in MEDLINE and Epistemonikos of systematic reviews and meta-analyzes of controlled clinical trials and casecontrol examining post-treatment infections with anti-TNF alpha, anti-CD20, anti-CD52, CTLA4-Ig and anti-integrins. The research was complemented by a review of: multicentre cohorts of biological users, the MMWR of the CDC, Atlanta, U.S.A., and national registers and scientific societies in which infectious complications derived from the use of biological therapies were mentioned.

Moderate to severe plaque psoriasis - treatment with drugs of the classic scheme

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Psoriasis in moderate grave plaque - immunobiological treatment

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

Immunotherapy-induced pneumonitis: cases report / Pneumonite induzida por imunoterapia antineoplásica: relato de casos

ABSTRACT Immunotherapy-induced pneumonitis is a rare complication with incidence estimated around 3%. This disease is difficult to diagnose and has great morbidity. For this reason, it became a challenge for oncologists and emergencists. We reviewed the case of five patients who used anti-PD1 (program cell death receptor antagonist 1) for antineoplastic treatment and developed treatment-induced pneumonitis. All patients had respiratory problems because of immunotherapy and presence of ground-glass radiologic change. Among all patients, only one had grade 5 pneumonitis, and delaying to begin corticosteroid therapy and worsening in clinical picture led to patient death. Other four patients with symptomatic grade 2 pneumonitis underwent corticosteroid therapy and had improvement in clinical and radiologic picture. Two patients were treated after an episode of pneumonitis, and no new pulmonary complications were observed until the end of this study. Immunotherapy-induced pneumonitis, although uncommon, can be potentially fatal. Medical team has the responsibility to pay attention for most common symptoms of the disease such as cough and dyspnea and conduct an early diagnosis and effective early treatment with corticosteroids.

RESUMO A pneumonite secundária à imunoterapia é uma complicação rara, com incidência estimada em cerca de 3%. No entanto, trata-se de uma intercorrência de difícil diagnóstico e com grande morbidade, que tem se tornado um desafio para oncologistas e emergencistas. Foram revisados os casos de cinco pacientes que fizeram uso de anti-PD1 (program cell death receptor antagonist 1) para tratamento antineoplásico e que evoluíram com quadro de pneumonite induzida pelo tratamento. Todos os pacientes apresentaram sintomas respiratórios em vigência de tratamento, com imunoterapia e presença de alteração radiológica em vidro fosco. Dentre estes pacientes, apenas um apresentou pneumonite grau 5, com atraso na introdução de corticoidoterapia, indo a óbito em decorrência do quadro. Os outros quatro pacientes apresentaram pneumonite grau 2, sintomática, sendo tratados com corticoidoterapia e evoluindo com melhora clínica e radiológica. Dois pacientes mantiveram o tratamento após o episódio de pneumonite, sem novas complicações pulmonares posteriores, até o momento. A pneumonite induzida por imunoterapia, apesar de ser um evento pouco frequente, pode acarretar grande morbidade, além de ser potencialmente fatal, cabendo à equipe médica ter atenção aos sintomas mais comuns, como tosse e dispneia, para diagnóstico precoce e tratamento efetivo, com uso precoce de corticoide.

Secukinumab para psoriasis en placa / Secukinumab for plaque psoriasis

INTRODUCCIÓN: Los tratamientos biológicos han aparecido como principal alternativa para el manejo de los pacientes con psoriasis en placa que no responden a tratamiento convencional, resultando necesario evaluar su real efectividad y seguridad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos 21 revisiones sistemáticas que en conjunto incluyeron diez estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que secukinumab logra mejoría clínica en pacientes con psoriasis en placa, aunque probablemente se asocia a efectos adversos graves.

INTRODUCTION: Biological treatments have appeared as the main alternative for the management of patients with plaque psoriasis that do not respond to conventional treatment. So, evaluating its actual efficacy and safety is needed. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 21 systematic reviews including ten studies overall, of which all were randomized trials. We concluded secukinumab achieves clinical improvement in patients with plaque psoriasis, although it is probably associated with serious adverse effects.

Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy / Infecção sistêmica e localizada por Candida spp. em pacientes reumatológicos em terapia anti-TNF

ABSTRACT Objective: To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Methods: Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and invasive procedures. All subjects were evaluated for clinical complaints; specific blood cultures were obtained for fungi and blood samples were collected for Candida spp. detection by polymerase chain reaction. Results: 194 patients [67 with rheumatoid arthritis (RA), 47 with ankylosing spondylitis (AS), 36 with juvenile idiopathic arthritis (JIA), 28 with psoriatic arthritis and 16 with other conditions] were included. The average age of patients was 42 ± 16 years, with 68 (35%) male and mean disease duration of 15 ± 10 years. Sixty-four (33%) patients were receiving adalimumab, 59 (30%) etanercept and 71 (36%) infliximab. Eighty-one percent of patients were concomitantly taking immunosuppressant drugs. At the time of the study, only one (0.5%) patient had localized fungal infection (vaginal candidiasis). None of the patients included had systemic candidiasis with positive blood cultures for fungi or PCR positive for Candida spp. in peripheral blood sample. Conclusions: This was the first study to assess the prevalence of invasive and localized fungal disease by Candida in a significant number of patients with rheumatic diseases on anti-TNF therapy, and demonstrated low risk of candidiasis, despite the high prevalence of immunosuppressive drug use.

RESUMO Objetivo: Avaliar a prevalência de infecção sistêmica e localizada por Candida spp. e sua possível associação com dados demográficos, manifestações clínicas e laboratoriais e terapêutica em pacientes com doenças reumatológicas em uso de anti-TNF. Métodos: Foram incluídos pacientes consecutivos com doenças reumatológicas em uso de agentes anti-TNF. Foram analisados os seguintes fatores de risco até quatro semanas antes do estudo: uso de antibioticoterapia, imunossupressores, hospitalização e procedimentos invasivos. Todos foram avaliados para queixas clinicas, coletaram hemocultura específica para fungos e amostras de sangue para pesquisa de Candida spp. por reação em cadeia de polimerase. Resultados: Foram incluídos 194 pacientes [67 com artrite reumatoide (AR), 47 espondilite anquilosante (EA), 36 artrite idiopática juvenil (AIJ), 28 artrite psoriásica e 16 outros]. A média de idade era de 42 ± 16 anos, com 68 (35%) do sexo masculino e média de duração de doença de 15 ± 10 anos; 64 (33%) pacientes usavam adalimumabe, 59 (36%) etanercepte e 71 (36%) infliximabe; 81% faziam uso concomitante de imunossupressores. No momento do estudo, apenas um (0,5%) paciente apresentou infecção fúngica localizada (candidíase vaginal). Nenhum dos pacientes incluídos apresentou candidíase sistêmica com hemocultura positiva para fungos ou PCR positiva para Candida spp. em amostra de sangue periférico. Conclusões: Este foi o primeiro estudo que avaliou prevalência de doença fúngica invasiva e localizada por Candida em um expressivo número de pacientes reumatológicos em terapia anti-TNF e demonstrou baixo risco de candidíase, apesar da alta prevalência de uso de imunossupressores.

Fertilidad y embarazo en pacientes con enfermedades inflamatorias intestinales / Fertility and pregnancy in patients with inflamatory bowel disease

Las Enfermedades Inflamatorias Intestinales (EII) son entidades crónicas del tracto digestivo, que afectan frecuentemente a pacientes en edad reproductiva. Debido a las características de estas enfermedades y su tratamiento, existen múltiples desafíos. En este artículo, revisamos la evidencia más reciente con respecto a fertilidad y embarazo en pacientes con EII. En general, existe evidencia de que pacientes con EII tienen una mayor tasa de complicaciones durante el embarazo con respecto a pacientes sin EII. Sin embargo, esta diferencia está directamente asociada al grado de actividad de la enfermedad. La mayor parte de los fármacos hoy usados en el tratamiento de EII son considerados seguros durante el embarazo y se recomienda continuarlos, sobre todo considerando que el mayor riesgo de complicaciones está asociado a una enfermedad activa. Sin embargo es importante considerar las opciones caso a caso. Las dos grandes excepciones son metotrexato y talidomida que están completamente contraindicadas. La recomendación más importante es educar a toda paciente con EII en edad reproductiva, explicando que el embarazo debe llevarse a cabo cuando la enfermedad esté controlada y que la probabilidad de complicaciones está relacionada con el grado de actividad y severidad de la EII. Los médicos tratantes deben educar a las pacientes, enfatizando el seguimiento de los controles y tratamiento

Inflammatory bowel diseases (IBD) are chronic conditions of the gastrointestinal tract that can affect patients during their childbearing years. Considering the characteristics of disease and the medications used to treat it, several issues arise in the care of these patients when they attempt or achieve conception. We review the most current evidence concerning fertility and pregnancy outcomes in patients with IBD. With the exception of those women who undergo pelvic surgery, patients with IBD have no decreased fertility. Overall, when looking at obstetrical outcomes, patients with IBD have worse outcomes when compared to controls, but this is usually driven by disease activity at conception. While most medications used to treat IBD are low risk, some precautions need to be taken and the risk-to-benefit ratio needs to be considered on a case-to-case basis. In general, aminosalicylates and thiopurines should be continued, but methotrexate and thalidomide are contraindicated. Anti-tumor necrosis factor agents are considered safe to continue but full monoclonal antibodies do cross the placenta. As a general rule, it is important to counsel women that conception is optimal when disease is in remission, as adverse obstetrical outcomes are directly associated with disease activity. Clinicians need to educate patients before, during and after conception, emphasizing treatment compliance.

Alopecia secondary to anti-tumor necrosis factor-alpha therapy

Biologic drugs represent a substantial progress in the treatment of chronic inflammatory immunologic diseases. However, its crescent use has revealed seldom reported or unknown adverse reactions, mainly associated with anti-tumor necrosis factor (anti-TNF). Psoriasiform cutaneous reactions and few cases of alopecia can occur in some patients while taking these drugs. Two cases of alopecia were reported after anti-TNF therapy. Both also developed psoriasiform lesions on the body. This is the second report about a new entity described as 'anti-TNF therapy-related alopecia', which combines clinical and histopathological features of both alopecia areata and psoriatic alopecia. The recognition of these effects by specialists is essential for the proper management and guidance of these patients.