Network meta-analysis on efficacy and safety of different biological agents in treatment of rheumatoid arthritis / 中国组织工程研究

OBJECTIVE:There are many kinds of biological agents for the treatment of rheumatoid arthritis in clinic,but the differences in therapeutic efficacy and safety are still unclear.The purpose of this study is to compare the differences in effectiveness and safety of different biological agents for the treatment of rheumatoid arthritis. METHODS:CNKI,VIP,WanFang,China Biomedical Literature System,PubMed,Cochrane Library,Web of Science,and Embase databases were searched to collect the randomized controlled trials on biological agents for rheumatoid arthritis that meet the requirements from inception to October 1,2022.The literature was selected by EndNote software,and the quality of the included literature was evaluated by RevMan 5.3 software.The software Stata 14.2 was used for direct meta-analysis and network meta-analysis of ACR20(American College of Rheumatology 20%response),ACR50(American College of Rheumatology 50%response),ACR70(American College of Rheumatology 70%response),erythrocyte sedimentation rate,and adverse reactions. RESULTS:Totally 39 articles were included,including 5 low-risk articles,4 high-risk articles,and the remaining 30 articles contained unknown risk bias,with a total of 13 treatment measures.The results of network meta-analysis:(1)In ACR20,infliximab combined with methotrexate(OR=5.54,95%CI:1.33-23.01,P<0.05),abatacept+methotrexate tablets(OR=3.21,95%CI:1.13-9.10,P<0.05),and tocilizumab(OR=2.95,95%CI:1.61-5.44,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR20 was:infliximab+methotrexate tablets>abatacept+methotrexate tablets>tocilizumab>certlizumab>etanercept+methotrexate tablets.(2)In the aspect of ACR50,etanercept combined with methotrexate tablets(OR=4.04,95%CI:2.13-7.66,P<0.05),infliximab combined with methotrexate tablets(OR=4.79,95%CI:1.19-19.26,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.54,95%CI:1.36-9.22,P<0.05)had better therapeutic effects than methotrexate tablets.The probabilistic ranking of ACR50 was:etanercept+methotrexate tablets>infliximab+methotrexate tablets>tocilizumab+methotrexate tablets>tocilizumab>certlizumab+methotrexate tablets.(3)In terms of ACR70,the therapeutic effects of infliximab combined with methotrexate tablets(OR=8.00,95%CI:2.31-27.69,P<0.05),etanercept combined with methotrexate tablets(OR=4.26,95%CI:2.51-7.21,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.51,95%CI:1.82-6.80,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR70 was infliximab+methotrexate tablets>etanercept+methotrexate tablets>tocilizumab+methotrexate tablets>certlizumab>adalimumab+methotrexate tablets.(4)In erythrocyte sedimentation rate,etanercept combined with methotrexate tablets(SMD=-9.23,95%CI:-16.55 to-1.92,P<0.05)was better than etanercept and methotrexate tablets(SMD=14.59,95%CI:7.28-21.91,P<0.05).The probabilistic ranking of erythrocyte sedimentation rate was etanercept+methotrexate tablets>infliximab+methotrexate tablets>etanercept>adalimumab+methotrexate tablets>methotrexate tablets.(5)In terms of adverse reactions,placebo(OR=0.62,95%CI:0.39-0.99,P<0.05)was better than infliximab and certlizumab(OR=0.44,95%CI:0.25-0.78,P<0.05).The probabilistic ranking of adverse reactions was placebo>infliximab>etanercept+methotrexate tablets>certlizumab>etanercept. CONCLUSION:Based on evidence from 39 randomized controlled trials,infliximab combined with methotrexate tablets(highly recommended)can be the first choice in clinic,and etanercept combined with methotrexate tablets(highly recommended)can be the second choice in terms of good effectiveness and safety.

Signal mining and evaluation of adverse events of four biological agents for the treatment of inflammatory bowel disease / 中国药房

OBJECTIVE To provide reference for safe drug use in the clinic by mining the adverse drug event （ADE） signals of 4 kinds of biological agents for the treatment of inflammatory bowel disease （IBD）. METHODS ADE data of infliximab， adalimumab， ustekinumab and vedolizumab were collected from the FDA adverse event reporting system between the first quarter in 2004 and the fourth quarter in 2022， and were mined by using reporting odds ratio （ROR） method and proportional reporting ratio （PRR） method. The system organ class （SOC） was used for the classification and statistics of drug ADE terminology. RESULTS & CONCLUSIONS A total of 65 173， 247 894， 37 596 and 6 134 ADE reports were retrieved for the above 4 biologic agents， involving 1 664， 1 731， 588， 303 ADE signals and 27， 27， 24， 26 SOC， respectively. The largest number of ADE reported of infliximab were various musculoskeletal and connective tissue diseases， and the signal intensity of disseminated tuberculosis was stronger. The largest number of ADE reported of adalimumab were systemic disease and various reactions at the administration site， and the signal intensity of papular at the injection site was stronger. The largest number of ADE reported of ustekinumab were various injuries， poisoning and operation complications， and the signal intensity of latent tuberculosis was slightly stronger. The largest number of ADE reported of vedolizumab were systemic diseases and various reactions at the administration site， and the signal intensity of shorter treatment response time was stronger. When clinically administering the four drugs， it is crucial to pay close attention to common ADEs and other ADE not mentioned in the drug label. For infliximab， clinicians should exercise caution due to the potential risk of synovitis and basal cell carcinoma； when prescribing adalimumab， caution should be exercised due to ADEs related to synovitis and hernia； for ustekinumab， the ADE associated with hepatobiliary diseases should be vigilant； for vedolizumab， clinicians should be vigilant for blood in the stool， increasing frequency of defecation. Except for ustekinumab， the other 3 biological agents also require attention for ADE associated with pregnancy.

Estamos prontos para múltiplas trocas entre produtos de referência e biossimilares? / Are we ready for multiple switches between reference products and biosimilars?

ABSTRACT Inflammatory bowel diseases (IBD) currently impose an immense social and economic burden on society in terms of both direct and indirect healthcare costs. Their incurable and progressive nature results in an unavoidable lifetime expense. The introduction of infliximab more than two decades ago had revolutionized IBD treatment. Nowadays, while biologic drugs comprise various vital therapeutic options for patients, they can be associated to significant costs to healthcare systems. The most crucial benefit of biosimilars is that they bring more significant cost reduction and increase access to advanced therapies. They also allow the treatment of newly diagnosed patients and dose optimization for those who need it. There is an inverse relationship between price and demand for treatment with biologics. For a more significant reduction in cost to be possible, greater use of biosimilars is necessary. For this to occur, it is imperative not only to use biosimilars in naïve patients but also to switch to biosimilars in those patients who have started therapy with reference biologics. At present, randomized and observational studies have demonstrated effectiveness and safety results in recommending a single switch between a reference product and a biosimilar, and vice versa. The purpose of this manuscript is to review the literature and discuss whether scientific evidence is enough to support multiple switches of biologics and biosimilars in IBD patients.

Evaluation of proactive therapeutic drug monitoring application in infliximab users in ulcerative colitis

Objective: To evaluate the application of proactive pro-drug therapy (TDM) at week six in users of infliximab therapy in ulcerative colitis patients and to analyze the need for further disease optimization. Method: This is a retrospective analysis that will be carried out simultaneously at the Hospital de Clínicas de Passo Fundo and at the Endoclin Diagnostic Center in the city of Passo Fundo, with secondary data collection between January 2020 and May 2022. The sample included patients from both sexes, regardless of age, who are being followed up in the services mentioned above, by signing the informed Free and Clarified Consent Term. Results: 63.2% of patients required optimization of their treatment based on the serum level assessment at week six. Conclusion: Proactive TDM performed at week six benefits patients in order to complete indications for treatment to avoid lack of drug response and complications from the disease. (AU)

Therapeutic drug monitoring in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a problem that directly affects the quality of life of patients suffering from this condition. Monitoring the serum level of infliximab (IFX) (TDM) is an important tool for guiding therapeutic decisions in IBD patients. The purpose of this study was to determine the significance of quantitatively measuring the serum level of IFX (TDM) and antibody to IFX (ATI). Methods and materials: Prospective observational study involving 40 IBD patients on IFX therapy, including 14 Proactive (week 06 of the induction phase) and 26 Reactive (maintenance phase). Immediately prior to the infusion, blood samples were drawn and measured using a Bulhlmann rapid test instrument. Serum concentrations of IFX were categorized as supratherapeutic (>7.0 micrograms/ml), therapeutic (between 3.0 and 7.0 micrograms/ml), and subtherapeutic (3.0 micrograms/ml). When the serum concentration of IFX was 3 mcg/ml (subtherapeutic), the ATI was measured. 25 patients with CD and 15 patients with UC were evaluated. Only three of the twenty patients with subtherapeutic serum levels had a positive ATI, and both were reactive; two had CD and one had UC. There was a statistically significant difference between reactive and proactive patients with respect to levels of CRP (p = 0.042), with proactive DNS patients suffering greater alterations in CRP and albumin. (AU)

The Effects of White Tea (Camellia Sinensis) and Infliximab Against Cisplatin- Induced Testicular Damage via Oxidative Stress and Apoptosis / Efectos del Té Blanco (Camellia Sinensis) e Infliximab Contra el Daño Testicular Inducido por Cisplatino a Través del Estrés Oxidativo y la Apoptosis

SUMMARY: Cisplatin (Cis) is an important chemotherapeutic agent used in cancer treatment. Males exposed to Cis were reported to exhibit testicular toxicity. Cis-induced testicular toxicity is mediated by oxidative stress, inflammation, testosterone inhibition and apoptosis. Accordingly, this study was conducted to evaluate the potential protective roles of infliximab (IFX), which is an anti- TNF-a agent, and of white tea (Camellia sinensis), which is known to possess antioxidant, anti-apoptotic, and anti-inflammatory effects, against Cis-induced testicular toxicity in rats. Rats were randomly assigned into five groups as follows: control group, Cisplatin (7 mg/kg) treatment group, Cisplatin (7 mg/kg) + infliximab (7 mg/kg) treatment group, cisplatin + white tea (WT) treatment group, and Cisplatin+ WT+IFX combined treatment group. In the present study, Cis exposure reduced the sperm count. It also increased testicular oxidative stress as well as the levels of inflammatory and apoptotic markers. Histopathological assays supported the biochemical findings. Treatment with IFX and/or WT restored testicular histology, preserved spermatogenesis, suppressed oxidative stress and apoptosis, and significantly ameliorated Cis-induced damage. It was concluded that white tea and infliximab could potentially serve as therapeutic options for the protection of testicular tissue against the harmful effects of Cis.

El cisplatino (Cis) es un importante agente quimioterapéutico utilizado en el tratamiento del cáncer. Se informó que los hombres expuestos a Cis exhibieron toxicidad testicular. La toxicidad testicular inducida por Cis está mediada por el estrés oxidativo, la inflamación, la inhibición de la testosterona y la apoptosis. En consecuencia, este estudio se realizó para evaluar las posibles funciones protectoras de infliximab (IFX), un agente anti-TNF-α, y del té blanco (Camellia sinensis), conocido por sus propiedades antioxidantes, antiapoptóticas y anti-TNF-α -efectos inflamatorios, contra la toxicidad testicular inducida por Cis en ratas. Cinco grupos de ratas se asignaron al azar de la siguiente manera: grupo control, grupo de tratamiento con cisplatino (7 mg/ kg), grupo de tratamiento con cisplatino (7 mg/kg) + infliximab (7 mg/kg), grupo de tratamiento con cisplatino + té blanco (WT), y grupo de tratamiento combinado Cisplatino+ WT+IFX. En el presente estudio, la exposición a Cis redujo el conteo de espermatozoides. También aumentó el estrés oxidativo testicular, así como los niveles de marcadores inflamatorios y apoptóticos. Los ensayos histopatológicos respaldaron los hallazgos bioquímicos. El tratamiento con IFX y/o WT restauró la histología testicular, preservó la espermatogénesis, suprimió el estrés oxidativo y la apoptosis, y mejoró significativamente el daño inducido por Cis. Se concluyó que el té blanco y el infliximab podrían potencialmente servir como opciones terapéuticas para la protección del tejido testicular contra los efectos nocivos de Cis.

Recurrent acute coronary syndrome after infliximab infusion in a patient with rheumatoid arthritis: Case report

Case description: A 61-year-old male patient with uncontrolled rheumatoid arthritis presented acute coronary syndrome on three occasions, less than 48 hours after infliximab infusion. Clinical findings: He presented with ST-elevation myocardial infarction on two occasions and non-ST-elevation acute coronary syndrome on one, with the identification of multivessel coronary disease. Treatment and outcome: Coronary intervention was performed with thrombus aspiration, medicated stent implantation, medicated balloon angioplasty, discontinuation of infliximab, and modification and optimization of cardiovascular pharmacological management. Clinical relevance: Patients with rheumatoid arthritis have subclinical cardiovascular disease and increased cardiovascular risk. The evidence regarding the relationship between infliximab and ischemic heart disease is controversial. A wide clinical spectrum of cardiac involvement with infliximab infusion is found in case reports, ranging from stable angina to ST-segment elevation acute coronary syndrome. The pathophysiology is not elucidated, with hypotheses proposing plaque rupture, allergic reactions, and vasoconstriction as possible disease mechanisms. The direct association between infliximab infusion and acute coronary syndrome needs more clinical research to optimize the management and prognosis of patients presenting with this type of complication.

Descripción del caso: Paciente masculino de 61 años con artritis reumatoide no controlada, en manejo con infliximab, quién presentó en tres oportunidades síndrome coronario agudo menos de 48 horas posterior a la aplicación del medicamento. Hallazgos clínicos: Presentó infarto con elevación del ST en dos ocasiones y síndrome coronario agudo sin elevación del ST en una oportunidad, encontrándose enfermedad coronaria multivaso. Tratamiento y resultado: Se realizó intervención coronaria con tromboaspiración, implante de stents medicados y angioplastia con balón medicado, suspensión del infliximab y modificación y optimización de manejo farmacológico cardiovascular. Relevancia clínica: Los pacientes con artritis reumatoide tienen enfermedad cardiovascular subclínica y mayor riesgo cardiovascular. La evidencia respecto a la relación entre infliximab y cardiopatía isquémica es controversial. En reportes de caso se encuentra un amplio espectro clínico de compromiso cardíaco con la infusión de infliximab, que va desde la angina estable hasta el síndrome coronario agudo con elevación del segmento ST. La fisiopatología no está claramente dilucidada, con hipótesis que proponen la ruptura de placa, reacciones alérgicas y la vasoconstricción como posibles mecanismos de enfermedad. La asociación directa entre la infusión de infliximab y el síndrome coronario agudo necesita más investigación clínica con el fin de optimizar el manejo y pronóstico de los pacientes que presentan este tipo de complicaciones.

Body composition and functional capacity in patients with Crohn's disease using Infliximab / Composição corporal e capacidade funcional de pacientes com doença de Crohn em uso de Infliximabe

Rationale: the use of anti-TNFα therapy, such as Infliximab (IFX), in patients with Chron's disease (CD) can lead to changes in body composition. Objective: to evaluate the body composition and functional capacity of patients with CD. Method: Cross-sectional study with patients with CD in clinical remission using IFX. For anthropometric evaluation, it was measured: weight, height and waist circumference; functional capacity by the hand grip strength test and body composition by bioelectric impedance. After that, the fat-free mass index and body fat index were calculated. Continouns variables were analyzed by Pearson or Spearman coefficient. For the multiple linear regression model, the time of use of IFX was used as a dependent variable and waist circumference, fat-free mass index, phase angle and handgrip strength were used as independent variables. Results: forty-three patients were evaluated, with an average of 43.1± 13.5 years of age. Of the total, 44.2% were overweight and 44.2% had increased waist circumference, 58.1% were classified with high to very high fat-free mass, 30.2% were below the adequacy parameter for fat-free mass index and 11.6% had reduced functional capacity. Conclusion: overweight, as well as increased waist circumference and body fat, is common in CD patients in clinical remission using Infliximab. Most patients had preserved functional capacity, however there wasn't association with time of use of IFX.

Introdução: o uso de terapia anti-TNFα, como o Infliximabe (IFX), em pacientes com doença de Chron (DC) pode levar a alterações na composição corporal. Objetivo: avaliar a composição corporal e capacidade funcional de pacientes com DC. Metodologia: estudo transversal com pacientes com DC em remissão clínica, em uso de IFX. Foi realizada avaliação antropométrica (peso, estatura e circunferência da cintura); avaliação de capacidade funcional (teste de força de pressão manual); e avaliação de composição corporal (impedância bioelétrica) com cálculo do índice de massa livre de gordura e índice de gordura corporal. Variáveis contínuas foram analisadas pelo coeficiente de correlação de Pearson ou Spearman. Para o modelo de regressão linear múltipla, o tempo de uso do IFX foi utilizado como variável dependente e circunferência da cintura, índice de massa magra, ângulo de fase e força de preensão manual foram utilizados como variáveis independentes. Resultados: foram avaliados 43 pacientes, com média de idade de 43,1± 13,5 anos. 44,2% estavam acima do peso e 44,2% possuíam circunferência da cintura aumentada, 58,1% foram classificados com índice de gordura corporal de alto a muito alto, 30,2% estavam abaixo do parâmetro de adequação para o índice de massa livre de gordura e 11,6% apresentaram capacidade funcional reduzida. Conclusão: o excesso de peso e o aumento de circunferência da cintura e gordura corporal é frequente em pacientes com DC em remissão clínica e em uso de IFX. A maioria dos pacientes apresentou capacidade funcional preservada, porém não houve associação com o tempo de uso do IFX.

The efficacy of anti–TNF-? agents in the treatment of juvenile idiopathic arthritis-associated uveitis in a pediatric cohort

Purpose: Biologic therapy has shown promising control in children with often intractable juvenile idiopathic arthritis (JIA)?associated uveitis (JIA?U). Methods: This is a retrospective cohort study of 35 eyes of 35 children who received biologics for JIA?U. Pretreatment and posttreatment data (at 3, 6, 9, 12, 18, 24, and >24 months) were analyzed to determine functional success (stable/improved visual acuity), quiescence success (?0.5 cells in the anterior chamber), complete steroid success (termination of systemic, periocular therapy and decreased topical drops to ?2/day) or systemic steroid success (termination of systemic steroids only), and complete success (all of the above). Results: This study included 35 eyes up to 12 months and 21 eyes beyond 24 months. Steroid?sparing, functional, and quiescence success showed a rate of success of 52.43%, 77%, and 91%, respectively, at 12 months and 66.67%, 85.7%, and 76.2%, respectively, beyond 24 months. Complete success was 34.29% at 12 months, peaking at 18 months (65.62%) and reached 57.14% beyond 24 months. In their final follow?up, the best corrected visual acuity (BCVA) remained the same in 45.71%, improved in 37.14%, and worsened in 17.14% children. Conclusion: Biologic therapy is effective in JIA?U, especially in termination of systemic steroids, stabilization of vision, and maintaining quiescence

Clinical profile and management with immunosuppressants and biologics in Behcet’s uveitis: A cohort of 25 patients from a tertiary eye care center in South India

Purpose: To report the clinical profile of Behcet’s disease and its management with immunosuppressants and biologics in a cohort of 25 patients from a tertiary eye care center in South India. Methods: This was a retrospective, observational study. Records of 45 eyes of 25 patients between January 2016 and December 2021 were retrieved from the hospital database. Complete ophthalmic evaluation and systemic examination by the rheumatologist with appropriate investigations had been done. Results were analyzed using Statistical Package for the Social Sciences (SPSS) software. Results: Males (19, 76%) were found to be more affected than females (6, 24%). Mean age of presentation was 27.68 ± 11.08 years. Twenty patients had bilateral involvement (80%), and unilateral involvement was seen in five patients (20%). Seven eyes of four patients (16%) had isolated anterior uveitis, out of which one patient had unilateral and three patients had bilateral involvement. Twenty?six eyes of 16 patients (64%) had posterior uveitis, out of which six patients had unilateral and 10 had bilateral involvement. Twelve eyes of seven patients (28%) had panuveitis, out of which two patients had unilateral and five had bilateral involvement. Hypopyon was seen in five eyes (11.1%) and posterior synechiae in seven eyes (15.55%). Posterior segment findings included vitritis (24.44%), vasculitis (17.78%), retinitis (17.78%), disc hyperemia (11.11%), and disc pallor (8.89%). Steroids alone were given in five patients (20%) and intravenous methylprednisolone (IVMP) was given in four patients (16%). Immunosuppressive agents along with steroids were given in 20 patients (80%), of which azathioprine alone was given in seven patients (28%), cyclosporin alone was given in two patients (8%), mycophenolate mofetil alone was given in three patients (12%), combination of azathioprine and cyclosporin was given in six patients (24%), and combination of methotrexate and mycophenolate mofetil was given in one patient (4%). Biologics were given in 10 patients (40%) – adalimumab in seven patients (28%) and infliximab in three patients (12%). Conclusion: Behcet’s disease is an uncommon uveitis in India. Addition of immunosuppressants and biologics to conventional steroid therapy gives better visual outcomes.

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.

A avaliação de níveis sérios de infliximabe favorece a manutenção do tratamento em pacientes com doença inflamatória intestinal / The evaluation of infliximab trough level favors maintenance therapy of patients with inflammatory bowel disease

ABSTRACT Background: Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases that result from the deregulation of the mucosal immune system of the gastrointestinal tract. The use of biological therapies, including infliximab (IFX), is one of the strategies to treat both CD and UC. The IFX treatment is monitored by complementary tests, namely: fecal calprotectin (FC); C-reactive protein (CRP); and endoscopic and cross-sectional imaging. Besides, serum IFX evaluation and antibody detection are also used. Objective: To evaluate trough levels (TL) and antibodies in a population with inflammatory bowel (IBD) disease undergoing treatment with IFX, and the factors that might impact the treatment effectiveness. Methods: Retrospective, cross-sectional study with patients with IBD that were assessed for TL and antibody (ATI) levels in a southern Brazilian hospital, from June 2014 to July 2016. Results: The study assessed 55 patients (52.7% female) submitted to serum IFX and antibody evaluations (95 blood samples, 55 first test; 30 second test, and 10 as third testing. Forty-five (47.3%) cases were diagnosed with CD (81.8%), and ten with UC (18.2%). Serum levels were adequate in 30 samples (31.57%), subtherapeutic in 41 (43.15%), and supratherapeutic in 24 (25.26%). IFX dosages were optimized for 40 patients (42.10%), maintained for 31 (32.63%), and discontinued for 7 (7.60%). The intervals between infusions were shortened in 17.85% of the cases. In 55 tests (55.79%), the therapeutic approach was exclusively defined according to IFX and/or serum antibody levels. The assessment of patients one year later indicated that: the approach was maintained with IFX for thirty-eight patients (69.09%); the class of biological agent was changed for eight (14.54%); changes using the same class of biological agent occurred for two patients (3.63%); the medication was discontinued and not replaced for three patients (5.45%), and four patients (7.27%) were lost to follow-up. Conclusion: There were no differences in TL between groups with or without immunosuppressants, serum albumin (ALB), erythrocyte sedimentation rate (ESR), FC, CRP, and endoscopic and imaging examinations. Current therapeutic approach could be maintained for almost 70% of patients. Thus, serum and antibody levels are a useful tool in the follow-up of patients undergoing maintenance therapy and after treatment induction in patients with inflammatory bowel disease.

RESUMO Contexto: A doença de Crohn e a colite ulcerativa são doenças crônicas nas quais existem desregulação do sistema imune da mucosa do trato gastrointestinal. Uma das terapias usadas no tratamento dessas doenças são as medicações biológicas, entre elas o Infliximabe. A monitorização do tratamento dos pacientes com Iinfliximabe é feita por exames complementares: calprotectina fecal, pesquisa de atividade inflamatória, exames endoscópicos e imagem. Utiliza-se, também a dosagem do nível sérico do Infliximabe e a pesquisa de anticorpos. Objetivo: Analisar uma população com doenças inflamatórias intestinais, em tratamento com Infliximabe, submetida a avaliação do nível sérico do Infliximabe e do anticorpo, além de possíveis fatores que possam alterar ou contribuir no tratamento. Métodos: Trata-se de estudo retrospectivo, transversal, realizado por meio da revisão dos prontuários dos pacientes com doença inflamatória intestinal, em um hospital sul-brasileiro, no período de junho de 2014 até julho de 2016, que foram submetidos a avaliação dos níveis séricos de Infliximabe e do anticorpo. Resultados: Foram incluídos 55 pacientes, submetidos a dosagem do Infliximabe e do anticorpo, totalizando 95 coletas sanguíneas. Destes, 55 realizaram uma primeira coleta, 30 tiveram uma segunda amostra coletada e 10 coletaram uma terceira vez. Vinte e nove pacientes eram do sexo feminino (52,7%) e vinte e seis do sexo masculino (43.2%). Quarenta e cinco (47,3%) casos tinham diagnóstico de doença de Crohn (81,8%) e 10 de colite ulcerativa (18,2%). Em relação ao nível sérico encontrou-se nível adequado em 30 coletas (31,57%), subterapêutico em 41 coletas (43,15%) e supraterapêutico em 24 coletas (25,26%). A prescrição foi otimizada em 40 (42,10%) casos, mantida em 31 (32,63%) pacientes, suspensa em 7 (7,60%) ou que o intervalo entre as infusões fosse aumentado (17,85%). Na análise geral, em 53 coletas (55,79%) a conduta foi definida em função exclusivamente da dosagem sérica do Infliximabe e/ou do anticorpo, já em relação, apenas a primeira coleta obteve-se 33 (60%) pacientes. Avaliando-se os pacientes um ano após, obteve-se: em 38 (69,09%) pacientes a conduta foi mantida com Infliximabe e, em 8 (14,54%) foi optado por troca de classe, em 2 (3,63%) foi optado por troca da medicação na mesma classe, em 3 (5,45%) pacientes a medicação foi suspensa e não foi substituída e, em 4 (7,27%), perdeu-se o seguimento. Conclusão: Não encontrou-se diferença entre os níveis de Infliximabe entre os grupos com ou sem imunossupressor, albumina sérica, velocidade de hemossedimentação, Calprotectina, Proteína C reativa, exames endoscópicos e exames de imagem. A conduta atual pode ser mantida em quase 70% dos pacientes. Concluindo, a dosagem do nível sérico e do anticorpo é ferramenta útil no acompanhamento dos pacientes em terapia de manutenção e após a indução de tratamento em pacientes com Doença Inflamatória Intestinal.

Effect of Proactive and Reactive Therapeutic Drug Monitoring of Infliximab on Prognosis of Patients With Inflammatory Bowel Disease / 胃肠病学

Background:Therapeutic drug monitoring(TDM)has emerged as the important method for managing loss of response to infliximab.The effect of reactive and proactive TDM on clinical outcomes in inflammatory bowel disease(IBD)is uncertain.Aims:To evaluate the effect of proactive and reactive TDM of infliximab on the prognosis of patients with IBD.Methods:Clinical data of 99 IBD patients treated with IFX from January 2017 to October 2021 at the First Affiliated Hospital of Air Force Military Medical University were retrospectively analyzed,including 34 patients with proactive TDM and 65 patients with reactive TDM.The rate of treatment failure,IBD-related surgery or hospitalization were compared between the two groups.Logistic regression analysis was used to determine the independent risk factors of treatment failure.Results:The median follow-up of the patients was 21(13,32)months.The rate of treatment failure,IBD-related hospitalization rate of proactive TDM group were significantly lower than those of reactive TDM group(P<0.05),however,no significant difference in IBD-related surgery rate was found between two groups(P=0.081).Univariate analysis showed that ileocolonic resection before TDM,antibodies to infliximab(ATI)and reactive TDM might be correlated with treatment failure(P<0.05).Logistic regression analysis showed that reactive TDM(OR=5.829,95%CI:1.070-31.754,P=0.042)was the risk factor of treatment failure,and ileocolonic resection before TDM(OR=0.119,95%CI:0.019-0.736,P=0.022)was the protective factor of treatment failure.Conclusions:Compared with reactive TDM group,proactive TDM can significantly decrease the rate of treatment failure and IBD-related hospitalization rate.Reactive TDM is the risk factor of treatment failure,and ileocolonic resection before TDM is the protective factor of treatment failure.

Value of ultrasound in the diagnosis of secondary loss of response in pediatric Crohn′s disease treated with Infliximab / 中华超声影像学杂志

Objective:To investigate the value of ultrasound in the diagnosis of secondary loss of response in children with Crohn′s disease at maintenance stage treated with Infliximab.Methods:From January 2017 to December 2021, 51 children with Crohn′s disease who received Infliximab treatment and clinical response in the Beijing Children′s Hospital Affiliated to Capital Medical University were retrospectively analyzed, and whether there was secondary loss of response during the maintenance period was observed. The ultrasound examination results at the 14th week of treatment were collected to understand the correlation between ultrasound examination of intestinal wall and peri-intestinal healing and secondary loss of response.Results:A total of 15 out of 51 patients (29.4%) experienced secondary loss of response during treatment follow-up up to 54 weeks. Compared to children with continuous response, children with secondary loss of response had a thicker intestinal wall at week 14 of treatment [5.0 (3.8, 6.0)mm compared to 3.0 (2.0, 4.0)mm, P<0.001], and a higher proportion of intestinal wall stratified structure disappearance [8/15 (53.33%) compared to 3/36 (8.33%), P<0.001]. When intestinal wall thickness>3.0 mm, the sensitivity was 0.955, and the specificity was 0.483. The sensitivity and specificity of clear diagnosis of secondary loss of response in intestinal wall stratification were 0.727 and 0.825, respectively. The sensitivity and specificity of combined diagnosis for secondary loss of response were 0.933 and 0.611, respectively. Conclusions:At the 14th week of treatment with Infliximab in children with Crohn′s disease, the thickness of intestinal wall measured by ultrasound being more than 3.0 mm and the disappearance of intestinal wall statified structure provide important information for the diagnosis of secondary loss of response.

Infliximab treatment for Crohn′s disease: over 10 years of real-world research / 中华消化杂志

Objective:To evaluate the treatment persistence and long-time safety of infliximab (IFX) in the real-world in Chinese patients with Crohn′s disease (CD).Methods:From January 2009 to December 2021, at Sir Run Run Shaw Hospital, School of medicine, Zhejiang University, the clinical data of 1 309 patients with CD and treated with IFX were retrospectively analyzed, which included baseline data (gender, age at diagnosis, follow-up time, etc.), usage of IFX (the duration of treatment and situation of discontinuation) and adverse effects of IFX. Kaplan-Meier method was used to calculate the rate of consistent use of IFX and Cox regression was performed to analyze the influencing factors of treatment persistence. The chi-square test was used to analyze the associations between different factors and safety outcomes.Results:Among 1 309 patients, 936 (71.5%) were male, age at diagnosis was 28.7 years (28.1 years, 29.3 years). The follow-up time was 3.9 years (3.7 years, 4.0 years). The longest time of IFX treatment was 9.4 years. During the follow-up period, a total of 421 (32.2%) patients discontinued use of IFX and the sustained use of IFX at year 1, 3, 5 and 10 were 84.0%, 65.8%, 56.7% and 30.9% respectively. The results of Cox regression analysis revealed that patients with perianal lesions had an increased rate of sustained use of IFX ( HR(95% confidence interval) 0.75 (0.61, 0.92), P=0.006), while patients with adverse reactions had a decreased rate of sustained use of IFX ( HR(95% confidence interval) 1.23(1.01, 1.50), P=0.038). A total of 445 patients experienced adverse events, with an incidence rate of 34.0% (445/1 309). The acute infusion reaction was the most common side with an incidence rate of 13.7% (179/1 309), of which the rate of severe acute infusion reaction was 2.8% (5/1 309). The rate of infection was 10.5% (138/1 309), among which the rate of severe infection was 2.6% (34/1 309), and the rate of special pathogens infection was 5.5% (72/1 309). The rate of tuberculosis infection was 1.0% (13/1 309), and the most common affected site was the lungs (10 cases). The incidence of skin lesions (non-allergic, non-infectious and non-tumor skin) was 6.9% (90/1 309). The incidence of tumor was 1.1% (14/1 309). Patients who discontinued IFX due to adverse reactions accounted for 20.7% (92/445) of the patients with adverse reactions, among them patients who discontinued IFX due to acute infusion reaction, infections, neoplasms, delayed infusion reaction, skin lesions, abnormal liver function, hematological disorder, acute pancreatitis, joint pain and seizure accounted for 47.8% (44/92), 18.5% (17/92), 8.7% (8/92), 6.5% (6/92), 5.4% (5/92), 5.4% (5/92), 3.3% (3/92), 2.2% (2/92), 1.1% (1/92) and 1.1% (1/92), respectively. Among 14 patients with tumor, 11 were malignant tumors, 1 case of chronic leukemia was related with IFX. Multi-round of IFX treatment increased the risk of acute infusion reaction and severe acute infusion reaction, combination of immunosuppressants decreased the risk of liver injury, and IFX treatment for more than 1 year increased the risk of skin lesions ( χ2=6.16, 11.30, 18.20 and 9.47; P=0.013, =0.001, <0.001, =0.002). Conclusions:The rate of constant use of IFX is relatively high in Chinese Crohn′s disease patients. The long-term safety is good. Clinicians should pay more attention on the safety of patients receiving multiple rounds and long courses of IFX treatment.

Clinical application of Infliximab trough concentration and anti-drug antibody detection in the treatment of Crohn′s disease / 中华检验医学杂志

Objective:This work aims to analyze the relationship between the 14 weeks′ Infliximab (IFX) treatment trough blood-concentration of IFK and antibodies to infliximab (ATI) concentration and mucosal healing and infusion reactions in the treatment of Crohn disease (CD).Methods:A total number of 119 CD patients who started IFX treatment in DrumTower Hospital affiliated to Nanjing University Medical School from June 2018 to August 2022 were retrospectively included. General data, endoscopic scores, laboratory tests, 14 weeks′ IFX treatment trough concentration and ATI, as well as endoscopic reexamination and clinical responses during follow-up were collected. According to the endoscopic examination results at (32±4) weeks, the two groups′ patients were divided into the mucosal healing group and non-mucosal healing group. The 14 week IFX trough concentration and ATI situation of the two groups were compared. Multiple logistic regression analysis was applied to analyze the risk factors of (32±4) weeks mucosal healing, using (32±4) weeks mucosal healing as the categorical variable, receiver operating curve (ROC) was obtained, and the optimal critical value of 14 week IFX trough concentration was selected.Result:The results of the 14 weeks′ time point indicated that the end-point IFX concentration and baseline albumin concentration in the mucosal healing group ( n=70 cases) were all significantly higher than those in the non-mucosal healing group ( n=49 cases), with values of 5.0 (2.8, 8.7) μg/ml vs 2.2 (0.3, 4.3) μg/ml, (38.7±3.5) g/L vs (36.6±3.8) g/L, respectively. The 14 week effective trough IFX concentration of (32±4) weeks mucosal healing was 2.90 μg/ml, AUC value is 0.704. Multivariate logistic regression analysis showed that 14 week trough IFX concentration≥2.9 μg/ml ( OR=5.369, 95% CI 2.42-11.92) and baseline Alb≥35 g/L ( OR=7.378, 95% CI 2.18-24.99) were significantly correlated with mucosal healing. The positive rate of ATI at 14 weeks′ time-point was 15.1%, and the trough IFX concentration of all the patients with moderate to high concentrations of ATI ( n=21 cases) was<0.4 μg/ml. Twelve patients (10.1%) experienced infusion reactions, and 53 patients (44.5%) had discontinued IFX. Conclusion:The 14 week trough IFX concentration is closely related to (32±4) week endoscopic mucosal healing.

Biotherapy for acne inversa / 中华皮肤科杂志

With the increasing understanding of inflammatory pathogenesis of acne inversa, as well as with the development and application of biological agents in the treatment of autoimmune inflammatory diseases, some biological agents have shown good efficacy and potential for the treatment of acne inversa in clinical research and practice. This review mainly summarizes the research progress in biotherapy of acne inversa in recent years.

Literature analysis of drug-induced autoimmune hepatitis induced by tumor necrosis factor-α inhibitor / 中国药房

OBJECTIVE To analyze the characteristics of drug-induced autoimmune hepatitis （DIAIH） induced by tumor necrosis factor-α inhibitor （TNFi）， and to provide reference for clinical drug treatment. METHODS Retrieved from PubMed， Embase， China Academic Journal full-text Database， VIP and Wanfang database， the case reports of TNFi-induced DIAIH were collected to conduct descriptive analysis. RESULTS A total of 33 case reports involving 44 patients were collected， including 31 females and 13 males， with an average age of （41.14±2.20） years old， mostly aged 30 to 60 years （77.27%）. The primary diseases were Crohn disease （CD）， ulcerative colitis （UC） and rheumatoid arthritis （RA） （68.18%）. Of the 44 patients， 35 were treated with infliximab （IFX）， 7 with adalimumab， and 2 with etanercept. The dosage of 37 patients was within the scope of the instructions， and 31 received other drugs additionally； DIAIH mainly occurred ≤24 weeks after medication （68.18%）； 21 patients （47.73%） had no clinical manifestations； alanine aminotransferase and aspartate aminotransferase were abnormally elevated in all patients； anti-nuclear antibodies were positive in 38 patients. Except for 3 patients who required liver transplantation， all the other patients improved after drug withdrawal and/or symptomatic treatment such as glucocorticoid therapy. CONCLUSIONS TNFi- induced DIAIH is more common in female patients and can occur with conventional doses， with significant differences in occurrence time. However， the intervention measures are basically the same for DIAIH induced by different types of TNFi. Clinical use of TNFi， especially the use of IFX， requires close attention to the clinical manifestations， liver function and autoantibody level， and a detailed evaluation should be conducted to detect DIAIH as soon as possible. If liver function continues to not improve， it is necessary to stop taking medicine as soon as possible and receive symptomatic treatment to avoid developing acute or severe DIAIH or liver failure.

Advances in therapeutic drug monitoring of infliximab in patients with Crohn disease / 中国药房

Infliximab （IFX）， tumor necrosis factor-α inhibitor， is widely used in clinical practice for treating Crohn disease （CD）， but it is difficult to obtain the optimal therapeutic effect according to the conventional dose. It is recommended to perform therapeutic drug monitoring （TDM） for patients with poor therapeutic efficacy to guide clinical decisions. This paper reviews the pharmacokinetic characteristics of IFX， exposure-response relationship， the influencing factors of pharmacokinetic differences， and analytical methods in TDM. It is found that IFX doesn’t undergo liver or kidney metabolism， exhibits obvious exposure-response relationships in both the induction and maintenance phases of CD treatment； disease activity， albumin， antibodies to IFX （ATI） and other factors influence IFX’s exposure. It is recommended that trough concentration of IFX in the maintenance period should be kept above 3 μg/mL； the dose of IFX should be increased or medication interval should be shortened for patients with severe disease， low albumin levels and ATI formation， to promote therapeutic efficacy of IFX. It is suggested to use the same detection method for TDM of IFX in the same patient.

Effect of infliximab combined with miRNA-21 on lung cancer A549 cells / 中华内分泌外科杂志

Objective:To investigate the effect of infliximab combined with miRNA-21 on lung cancer A549 cells.Methods:A549 cells were cultured in vitro and then divided into four groups (blank group, infliximab group, miRNA-21 inhibitor group and combined treatment group) ; CCK-8 test was used to detect cell proliferation; Flow cytometry experiments was employed to detect apoptosis; Western blot was used to detect protein expression.Results:The survival rates of A549 cells in the miRNA-21 inhibitor group and the combined treatment group were 48.67%±2.83% and 25.69%±1.98%, which were significantly different ( P<0.001) ; The proportion of A549 apoptotic cells in the miRNA-21 inhibitor group and the combined treatment group were 46.73%±2.18% and 76.58%±3.67%, respectively, with significant differences ( P<0.001) ; The expression of Caspase-3 (1.21±0.26 vs 0.57±0.07) and Bad (1.08±0.11 vs 0.52±0.06) in the combined treatment group was significantly higher than that of the miRNA-21 inhibitor group in the detection of apoptosis-related proteins, and the expression of Bcl-2 was significantly reduced, with a significant difference ( P<0.001). In the combined treatment group, the expression levels of TNF-α (0.63±0.11 vs 1.23±0. 22, 1.18±0.17, 1.14±0.17) and NF-κB p65 (0.34±0.08 vs 1.31±0.09, 1.29±0.12, 1.11±0.06) were both reduced, and there was a significant difference compared with the other three groups ( P<0.001) . Conclusion:Infliximab combined with miRNA-21 inhibitors can play a synergistic role in lung cancer cells, inhibit the TNF-α/NF-κB signaling pathway, regulate the expression of the Bcl-2 family and Caspase-3, and promote apoptosis, thereby inhibiting lung cancer A549 cell proliferation.