RESUMO
Imetelstat is a first-in-class, 13-mer oligonucleotide telomerase inhibitor approved in the United States and European Union for the treatment of certain adult patients with lower-risk myelodysplastic syndromes (LR-MDS) with red blood cell (RBC) transfusion-dependent anemia. This post hoc analysis evaluated imetelstat immunogenicity and its association with the pharmacokinetics (PK), efficacy, and safety of imetelstat in patients with LR-MDS from the phase II/III IMerge study (NCT02598661). A validated, semi-quantitative 3-tiered method evaluated anti-drug antibodies (ADAs). Graphical and descriptive analyses evaluated ADA incidence and association with clinical outcomes. Of 166 evaluable patients who received 7.1 mg/kg imetelstat via a 2-h intravenous infusion every 4 weeks, 16.9% developed imetelstat ADAs (median [range] time to onset, 38 weeks [12-109]; ~8 treatment cycles). In ADA-positive patients, peak titer was low (median [range], 30 [10-160]). Evaluations showed no association of ADA positivity with imetelstat PK, nor any negative association with efficacy responses, including ≥ 8-week RBC-transfusion independence (TI), ≥ 24-week RBC-TI, hematologic improvement-erythroid, or duration of RBC-TI response. There was no apparent relationship between the onset of ADAs and loss of RBC-TI. The rates of any-grade or grade ≥ 3 treatment-emergent adverse events (TEAEs) were similar for both ADA groups, with no reported serious TEAEs or TEAEs causing death in ADA-positive patients. Infusion-related TEAEs were more frequent in ADA-positive patients, although the sample size was small. Overall, imetelstat ADAs did not appear to impact imetelstat benefit/risk profile in the LR-MDS population of IMerge, although the analysis is limited by the low incidence of imetelstat ADAs, resulting in a small ADA-positive group.
Assuntos
Inibidores Enzimáticos , Síndromes Mielodisplásicas , Oligonucleotídeos , Telomerase , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Oligonucleotídeos/farmacocinética , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/imunologia , Telomerase/antagonistas & inibidores , Adulto , Resultado do Tratamento , Idoso de 80 Anos ou mais , Transfusão de Eritrócitos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Infusões Intravenosas , Anticorpos/sangueRESUMO
RATIONALE: Tumor necrosis factor inhibitors (TNFi) infliximab and adalimumab are commonly used third-line treatments for chronic or refractory sarcoidosis. The utility of monitoring TNFi levels and anti-drug antibody (ADA) formation in sarcoidosis is unclear. This study aimed to identify factors associated with TNFi trough levels and ADA prevalence in real-world sarcoidosis patients. METHODS: We included sarcoidosis patients treated with TNFi for ≥3 months at an academic specialty clinic who had trough drug and ADA levels assessed due to suboptimal therapeutic response. Associations between TNFi levels and dosing, patient characteristics, concomitant medications, and presence of ADAs were analyzed by univariate analysis. RESULTS: 90 patients (median age 51 years, 66 % female, 60 % Black) met inclusion criteria (64 infliximab, 26 adalimumab). 66 % of patients were on at least 1 additional anti-sarcoidosis medication. The most common infliximab dose was 5 mg/kg every 6 weeks and adalimumab 40 mg weekly. Mean trough levels were 14.6ug/ml and 13.1ug/ml, respectively. ADAs were more prevalent in those on adalimumab (30.8 % vs 19.0 %). ADA presence was significantly associated with low infliximab (p < 0.001) and adalimumab levels (p < 0.001). For infliximab, concurrent use of second-line medications was associated with reduced prevalence of ADAs (8 % vs 38.9 %, p = 0.013) compared to patients on no additional immunosuppression. DISCUSSION: This is the largest reported cohort assessing TNFi drug and ADA levels in sarcoidosis to date. Prevalence of ADAs was high, particularly against adalimumab. Second-line therapy may reduce ADA formation. Monitoring TNFi drug and ADA levels may aid clinicians in managing patients with a suboptimal response to therapy.
Assuntos
Adalimumab , Anticorpos , Infliximab , Sarcoidose , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa , Humanos , Feminino , Adalimumab/imunologia , Adalimumab/uso terapêutico , Adalimumab/administração & dosagem , Infliximab/imunologia , Infliximab/uso terapêutico , Infliximab/administração & dosagem , Pessoa de Meia-Idade , Masculino , Sarcoidose/tratamento farmacológico , Sarcoidose/imunologia , Sarcoidose/sangue , Adulto , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Monitoramento de Medicamentos/métodos , Anticorpos/sangueRESUMO
Bead-based suspension arrays built with multiple antigens enable detection and identification of specific antibodies in human and animal serum. Here we describe how to use synthetic peptides as antigens in a serological Luminex assay. Biotinylated peptides immobilized on avidin beads are used to capture serum antibodies, which in turn are detected using a generic immunoglobulin-binding protein or broad anti-bird antibodies in resp. mammalian and avian sera. Background is suppressed by pre-blocking sera and by using a blocking agent during antibody capture. By employing an internal negative control, serum-specific cutoffs can be determined and/or signals can be normalized. The provided protocols allow creating multiplex bead-based suspension arrays using peptides as antigens to capture and detect specific serum antibodies from mammalians, including humans, and avian species.
Assuntos
Anticorpos , Antígenos , Peptídeos , Análise Serial de Proteínas , Humanos , Animais , Antígenos/imunologia , Antígenos/química , Peptídeos/imunologia , Peptídeos/química , Anticorpos/sangue , Anticorpos/imunologia , Microesferas , Análise Serial de Proteínas/métodos , Aves/imunologia , Biotinilação , Imunoensaio/métodosRESUMO
Previous research has highlighted the involvement of several human blood cells in skin cancer, but large-scale studies are lacking to explore their relationship and avoid confounding factors. Here, we comprehensively investigated the causal effect of blood cells on skin cancer subtypes across 4 different human microenvironments through 2-sample Mendelian randomization (MR) analysis and mediation analysis. Summary statistics of 91 human blood cells, 233 circulating metabolites, 731 immune cells, 46 antibody immune responses, 91 inflammatory cytokines, and 4 skin cancer traits (including cutaneous melanoma, nonmelanoma skin cancer, basal cell carcinoma, and squamous cell carcinoma) were derived from genome-wide association studies. The bidirectional 2-sample MR was used to determine the causality between exposures and outcomes. Additionally, comprehensive sensitivity analyses were performed to ensure the robustness of MR findings. Finally, the mediation analysis was applied to identify the role of blood cells in skin cancers mediated by 4 different microenvironments. MR revealed causal associations between 18 different types of human blood cells, 30 different types of circulating metabolites, 136 different types of immune cells, 17 different types of antibodies immune responses, 17 different types of inflammatory cytokines with skin cancers. Reverse MR analysis indicated skin cancers were causally associated with the levels of 4 different types of human blood cells. Mediation analysis revealed 19 mediation correlations during the causal effect from blood cells to skin cancers. Among them, 13 belonged to immune cells, 3 belonged to inflammatory cytokines, and 3 belonged to antibodies immune responses. Sensitivity analyses confirmed the consistency of these findings. This study represents the first comprehensive evaluation demonstrating causal relationships among human blood cells, circulating metabolites, immune cells, antibodies immune responses, inflammatory cytokines, and skin cancers, thereby providing novel insights and potential intervention targets for skin cancer treatment.
Assuntos
Anticorpos , Células Sanguíneas , Citocinas , Metaboloma , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Análise da Randomização Mendeliana , Citocinas/sangue , Análise de Mediação , Células Sanguíneas/imunologia , Estudo de Associação Genômica Ampla , Anticorpos/sangue , Melanoma/imunologia , Melanoma/genética , Melanoma/sangue , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/genéticaRESUMO
BACKGROUND AND AIMS: The development of antibodies to infliximab (ATI) is a major challenge in pediatric inflammatory bowel disease (IBD). This real-world study aimed to identify predictors of ATI, evaluate strategies to overcome ATI, and compare the durability of continuing infliximab (IFX) versus switching to adalimumab (ADA) after ATI development. METHODS: We retrospectively analyzed 194 pediatric IBD patients treated with IFX from 2010 to 2024. ATI titers were measured uniformly before each infusion. Demographic data, disease characteristics, ATI titers, infusion reactions, management strategies, and treatment durability were collected and analyzed. RESULTS: ATI developed in 52 of 194 patients (26.8 %), more frequently in Crohn's disease (31.2 %) than ulcerative colitis (16.1 %, p < 0.01), and was associated with female gender (57.7 % vs. 39.4 %, p = 0.03) and younger age at diagnosis. High-titer ATI (≥8 mcg/ml-eq) correlated with infusion reactions (56.5 % vs. 3.5 %, p < 0.001). ATI was managed with dose/interval adjustment (61.9 %), immunomodulator addition (16.7 %), or both (21.4 %). IFX continuation was successful in 71.4 %, especially in low-titer ATI (92.0 % vs. 41.2 %, p < 0.001). IFX durability after ATI was significantly longer (median 94 months) than ADA after switching (47 months, p < 0.01). CONCLUSIONS: About 27 % of pediatric IBD patients developed ATI to IFX. Personalized management can restore IFX efficacy and provides superior long-term outcomes compared to switching to ADA.
Assuntos
Adalimumab , Colite Ulcerativa , Doença de Crohn , Substituição de Medicamentos , Fármacos Gastrointestinais , Doenças Inflamatórias Intestinais , Infliximab , Humanos , Infliximab/imunologia , Infliximab/uso terapêutico , Infliximab/administração & dosagem , Feminino , Adalimumab/uso terapêutico , Adalimumab/imunologia , Adalimumab/administração & dosagem , Masculino , Estudos Retrospectivos , Criança , Adolescente , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Resultado do Tratamento , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Anticorpos/sangueRESUMO
INTRODUCTION: Rituximab (RTX) effectively manages myasthenia gravis (MG) by reducing relapse rates. Anti-Rituximab antibodies can develop in autoimmune diseases and may lead to RTX resistance. Although RTX infusions are increased, these antibodies do not influence the occurrence of adverse events. We conducted a retrospective study to evaluate how anti-drug antibodies (ADAs) impact treatment efficacy. METHODS: We reviewed 101 MG patients treated with first- or second-line RTX at Nice University Hospital from 2016 to 2023. Clinical assessments were performed quarterly using the Osserman Score (OS). Biological tests included ADA levels, RTX serum levels, CD19+CD27+ memory B cells, and CD19+ cell counts. RESULTS: Among 101 patients, 38 developed ADAs (37.6%), with a median onset of 433.5 days after the first infusion. The ADA group had significantly more RTX infusions (6.18 vs. 4.29, p=0.002) and more prolonged treatment durations (1908.26 vs. 1441.3 days, p=0.006). No differences in age, gender, or prior immunosuppression were noted. OS scores revealed no significant difference between ADA-positive and ADA-negative patients. The interval between infusions remained consistent before and after the appearance of ADAs. DISCUSSION: ADAs were found in one-third of MG patients treated with RTX, a higher prevalence than in other conditions. The number of RTX infusions was significantly greater in the ADA-positive group, and the longer is the treatment duration, the higher the likelihood of developing ADAs. Our findings suggest a need to reconsider routine ADA testing, as it does not correlate with clinical outcomes or infusion intervals. This raises questions about how to tailor maintenance therapy for MG patients stabilized with RTX.
Assuntos
Anticorpos , Autoanticorpos , Fatores Imunológicos , Miastenia Gravis , Rituximab , Humanos , Rituximab/imunologia , Rituximab/uso terapêutico , Rituximab/sangue , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/sangue , Miastenia Gravis/imunologia , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/sangue , Adulto , Autoanticorpos/sangue , Fatores de Tempo , Anticorpos/sangueRESUMO
Globally, opioid use disorder (OUD) presents a significant public health challenge linked to high mortality and disability rates. Heroin and other morphine derivatives are prevalent among abused opioids. Prolonged exposure to these substances in individuals with OUD can trigger an immune response, leading to the production of antibodies to morphine that may bind to morphine and potentially mitigate its rewarding effects. In our study, we analyzed serum samples from patients diagnosed with OUD to explore the nature and properties of antibodies to morphine, aiming to characterize the generation of antibodies to morphine due to long-term exposure to morphine. We observed varying titers of antibodies to morphine in OUD patients, absent in healthy controls, with both free morphine and morphine complexes detected bound to these antibodies, indicating less potency. Furthermore, our analysis revealed elevated levels of FoxP3, a critical transcription factor in regulatory T-cells (Tregs) responsible for maintaining immunosuppression. Concurrently, reduced levels of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6) indicated immunosuppressive activity. Notably, decreased antibody titers against the Acr1 protein of Mycobacterium tuberculosis suggested that morphine-induced immune suppression might compromise responses to other pathogens. These findings indicate that chronic morphine exposure not only suppresses host immunity but also induces the production of antibodies to morphine. Investigating whether these antibodies contribute to immune suppression or can be harnessed to combat morphine dependence presents an intriguing avenue for future research.
Assuntos
Anticorpos , Morfina , Transtornos Relacionados ao Uso de Opioides , Humanos , Morfina/imunologia , Morfina/administração & dosagem , Morfina/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/imunologia , Transtornos Relacionados ao Uso de Opioides/sangue , Transtornos Relacionados ao Uso de Opioides/patologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/genética , Masculino , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Feminino , Adulto , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/sangue , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/sangue , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/imunologia , Anticorpos/sangue , Anticorpos/imunologia , Pessoa de Meia-Idade , Analgésicos Opioides/imunologia , Tolerância Imunológica/efeitos dos fármacosRESUMO
INTRODUCTION: Human leukocyte antigen (HLA) DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNFα) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD aged <21 years enrolled in clinical outcomes of Methotrexate Binary Therapy in practice, a multicenter, prospective randomized trial of anti-TNFα monotherapy vs combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS: A trend toward increased treatment failure among HLA DQA1*05-positive participants was not significant (hazard ratio 1.58, 95% confidence interval [CI] 0.95-2.62; P = 0.08). After stratification by HLA DQA1*05 and by methotrexate vs placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70; P = 0.005). A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90-4.31, P = 0.09). After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03-0.55; P = 0.008). DISCUSSION: In a randomized trial of children with CD initiating anti-TNFα, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.
Assuntos
Doença de Crohn , Cadeias alfa de HLA-DQ , Imunossupressores , Metotrexato , Fator de Necrose Tumoral alfa , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Doença de Crohn/sangue , Doença de Crohn/genética , Metotrexato/uso terapêutico , Masculino , Feminino , Criança , Adolescente , Falha de Tratamento , Cadeias alfa de HLA-DQ/imunologia , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Estudos Prospectivos , Quimioterapia Combinada , Adalimumab/uso terapêutico , Adalimumab/imunologia , Imunossupressores/uso terapêutico , Anticorpos/sangue , Adulto JovemRESUMO
BACKGROUND: Antibodies have long served as fundamental tools in disease diagnosis and surveillance. Their utility as biomarkers has expanded beyond infectious diseases to encompass a wide range of health conditions. OBJECTIVES: This review aims to explore recent advancements in antibody biomarker discovery and their applications in diagnosing and monitoring diverse health conditions. It also examines the role of antibody surveillance in public health and epidemiological studies. METHODS: A comprehensive analysis of recent literature was conducted, focusing on studies that identify and characterize disease-specific antibodies. Particular attention was given to their relevance in autoimmune diseases, infections, cancers, and neurological disorders. CONTENT: The review highlights disease-specific antibody biomarkers and their clinical significance. It also discusses the utility and challenges of antibody-based surveillance in assessing disease prevalence, tracking immunity trends, and supporting One Health strategies. CONCLUSIONS: Recent advancements in antibody biomarker discovery demonstrate significant potential in improving early diagnosis, personalized treatment, and population-level health management. Antibody surveillance continues to play a pivotal role in guiding public health responses and understanding disease dynamics.
Assuntos
Anticorpos , Doenças Autoimunes , Biomarcadores , Neoplasias , Humanos , Biomarcadores/sangue , Anticorpos/imunologia , Anticorpos/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Neoplasias/diagnóstico , Neoplasias/imunologia , Animais , Vigilância ImunológicaRESUMO
Several studies have shown that infliximab and adalimumab ameliorate fatigue in inflammatory bowel disease. We investigated whether serum levels of these agents above or below a selected threshold influence fatigue severity. In this cross-sectional study, we measured serum concentrations (s-) of infliximab and adalimumab and corresponding anti-drug antibody levels. Therapeutic thresholds were defined as s-infliximab ≥ 5.0 mg/L and s-adalimumab ≥ 7.0 mg/L. Disease activity was assessed using the Harvey-Bradshaw Index for Crohn's disease, Partial Mayo Score for ulcerative colitis, and C-reactive protein (CRP) and faecal calprotectin levels for both conditions. Fatigue was assessed with the Fatigue Visual Analog Scale and Fatigue Severity Scale, and depression was evaluated with the Hospital Anxiety and Depression Scale, Depression subscale. Of 171 included patients (112 with Crohn's disease, 59 with ulcerative colitis), 66 (38.6%) were on infliximab and 105 (61.4%) were on adalimumab. Scores on the two fatigue scales were similar for serum values above versus below therapeutic thresholds for both drugs and did not differ with versus without anti-drug antibodies against either drug. CRP was numerically higher with infliximab levels below versus above the threshold (p = 0.06), whereas both CRP and faecal calprotectin were increased with adalimumab below versus above the threshold (p = 0.022, p = 0.0242). In patients with inflammatory bowel disease on maintenance therapy, s-infliximab and s-adalimumab levels below or above therapeutic thresholds or the presence of anti-drug antibodies did not affect fatigue severity. Trial Registration: ClinicalTrials.gov identifier: NCT02134054.
Assuntos
Adalimumab , Colite Ulcerativa , Doença de Crohn , Fadiga , Doenças Inflamatórias Intestinais , Infliximab , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adalimumab/uso terapêutico , Adalimumab/sangue , Adalimumab/imunologia , Anticorpos/sangue , Proteína C-Reativa/metabolismo , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Estudos Transversais , Fadiga/tratamento farmacológico , Fadiga/etiologia , Fadiga/sangue , Fezes/química , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , Infliximab/sangue , Infliximab/uso terapêutico , Infliximab/imunologia , Complexo Antígeno L1 Leucocitário/metabolismo , Índice de Gravidade de DoençaRESUMO
Immunological castration can be an alternative to traditional surgical castration. The active immunization against GnRH or kisspeptin has a castrating effect. To date, the fusion protein vaccine of combination with GnRH and kisspeptin have not been studied. Thus, the present study will develop a GnRH6-kisspeptin vaccine by genetic engineering method and investigate its immunocastration effect in male rats. Twenty 20-day-old male rats were randomly divided into two groups: the control group (n=10) and the immunization group (n=10). The initial immunization took place at week 0 followed by three booster doses administered intervals. The control group received an equivalent dose of white oil adjuvant. Orbital blood samples were collected at various time points following the initial immunization, at 0, 2, 4, 6, 8, 10 and 12 weeks, respectively. The entire left testis was weighed and its volume measured at week 12. Samples from the right testis were obtained for histological analysis. Serum levels of GnRH and kisspeptin antibodies, as well as testosterone levels were determined using ELISA. The results showed that the serum levels of GnRH and kisspeptin antibody titres of the immunized rats were significantly higher compared to the control group (P<0.05). Additionally, the testosterone concentration was effectively reduced following the intensified immunization. The testes of the immunized group exhibited a reduction in size and a significant decrease in the number of spermatogonia in the testicular tissue compared to the control group (P<0.05). These data indicate that the recombinant GnRH6-kisspeptin protein effectively induced immunological castration in rats.
Assuntos
Hormônio Liberador de Gonadotropina , Kisspeptinas , Proteínas Recombinantes de Fusão , Reprodução , Animais , Masculino , Kisspeptinas/imunologia , Kisspeptinas/genética , Hormônio Liberador de Gonadotropina/imunologia , Hormônio Liberador de Gonadotropina/genética , Testículo/efeitos dos fármacos , Testículo/imunologia , Proteínas Recombinantes de Fusão/imunologia , Testosterona/sangue , Ratos , Imunização , Anticorpos/sangue , Orquiectomia/métodos , Reprodução/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Derived from monocytes in the bone marrow, macrophages are large, innate immune cells that play a major role in clearing dead cells, debris, tumor cells, and foreign pathogens. The phagocytic capacity of monocytes versus macrophages is a concept that is not well understood. Here, we aim to examine a difference in the phagocytosis of monocytes versus macrophages, specifically M1/M2 macrophages, against various opsonized red cells using a modified and updated version of the established monocyte monolayer assay (MMA). Peripheral blood mononuclear cells (PBMCs) were isolated from donor buffy coats. Using purified monocytes, inflammatory M1 and anti-inflammatory M2 macrophages were produced by in vitro culture and polarization. M1/M2 cells were harvested and used in an MMA-like assay, which we refer to as the M-MA, to decipher clinically significant phagocytosis of various red cell antibodies. A phagocytic index (PI) > 5 was deemed clinically significant phagocytosis with the use of monocytes. A phagocytic index (PI) > 12 was deemed clinically significant phagocytosis with the use of M1/M2 macrophages. M2 macrophages demonstrate an increased ability to phagocytose opsonized RBCs compared to monocytes and M1s. The same weak antibody (anti-S) yields significant phagocytosis with only M2 macrophages (PI=43) but not M1s (PI=2) or monocytes (PI=0), and this was demonstrated repeatedly using various antibodies. The use of M2 macrophages instead of monocytes may allow for more accurate results as these cells are more phagocytic, offering further clinical relevance to the assay. Further studies with different antibodies to red blood cells, including validation of the monocyte-macrophage assay (M-MA) with antibodies having known clinical significance, may show the M-MA more useful to help predict clinically significant red cell alloantibodies and transfusion reactions. This method will advance the field of transfusion medicine and immunology.
Assuntos
Anticorpos , Eritrócitos , Macrófagos , Monócitos , Humanos , Macrófagos/imunologia , Macrófagos/citologia , Monócitos/imunologia , Monócitos/citologia , Fagocitose/imunologia , Eritrócitos/imunologia , Anticorpos/imunologia , Anticorpos/sangueRESUMO
BACKGROUND: The emergence of tumor necrosis factor inhibitors (anti-TNF) has considerably changed the management of inflammatory bowel disease (IBD) in patients who do not respond to traditional therapies. This study assesses the prevalence of anti-TNF drug levels (DLs) and antibodies (ATAbs) in patients with IBD in Saudi Arabia and explores their associations with IBD type and prior anti-TNF failure. METHODS: This cross-sectional study included patients aged 14-75 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), treated with anti-TNF medications at King Fahad Medical City over January 2016 to December 2022. Data were analyzed using descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson's Chi-squared test, and multinomial logistic regression. RESULTS: Among 392 patients with IBD (median age, 31 years), 75.8% were diagnosed with CD and 24.2% with UC. Anti-TNF levels were subtherapeutic in 27.0% patients, therapeutic in 21.5%, and supratherapeutic in 51.5%. ATAbs were negative in 73.1% patients, weakly positive in 9.8%, and positive in 17.1%. Subtherapeutic anti-TNF levels were significantly associated with positive ATAbs ( P < 0.001). Prior anti-TNF therapy failure was observed in 37.2% cases, with 15.3% showing immunogenicity. No significant demographic differences were noted across ATAbs groups. CONCLUSION: We highlight the prevalence of subtherapeutic and supratherapeutic anti-TNF levels among patients with IBD in Saudi Arabia and their association with ATAbs. The findings underscore the importance of monitoring anti-TNF DLs and ATAbs to optimize treatment outcomes in IBD management. Future research should focus on the longitudinal impact of these factors and explore genetic predictors of treatment response.
Assuntos
Anticorpos , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa , Humanos , Estudos Transversais , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Arábia Saudita/epidemiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem , Adolescente , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Doença de Crohn/sangue , Prevalência , Idoso , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/sangue , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Colite Ulcerativa/sangue , Infliximab/imunologia , Infliximab/sangue , Infliximab/uso terapêutico , Inibidores do Fator de Necrose Tumoral/sangue , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Inibidores do Fator de Necrose Tumoral/imunologia , Adalimumab/imunologia , Adalimumab/sangue , Adalimumab/uso terapêutico , Anticorpos/sangue , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêuticoRESUMO
OBJECTIVES: Hepatic fibrosis is a common pathological basis for many chronic liver diseases and can progress to cirrhosis, a leading cause of mortality in liver diseases. Early identification and reversal of hepatic fibrosis are key in the treatment of chronic liver disease. This study aims to compare the expression levels of serum core fucosylated low molecular weight kininogen (LMWK-Fc) and alpha-galactosylated (α-Gal) antibodies in patients with hepatic fibrosis at different stages, and to evaluate their diagnostic efficacy for hepatic fibrosis. METHODS: A retrospective analysis was conducted on 275 patients with chronic liver disease who visited the Department of Infectious Diseases at the Second Xiangya Hospital of Central South University between June 2022 and March 2023. Among these, 115 patients underwent liver biopsy. Based on the extent of collagen deposition and its impact on liver structure and microcirculation, patients were staged from 0 to 4: S0 (no significant collagen deposition in liver tissues; liver structure and microcirculation are normal), S1 (mild collagen deposition in liver tissues, with partial disruption of lobule structure, but microcirculation remains largely normal), S2 (moderate collagen deposition in liver tissues, with partial disruption of lobule structure and microcirculation), S3 (extensive collagen deposition in liver tissues, with substantial disruption of lobule structure and microcirculation), and S4 (development of cirrhosis, with heavy collagen deposition, complete disruption of lobule structure, and severe impairment of microcirculation). Patients were grouped as no fibrosis (S0), fibrosis (S1-S2), and significant fibrosis (S3-S4). For the 160 patients without liver biopsy, they were categorized based on liver stiffness measurement (LSM) value: no fibrosis (F0: LSM<7.3 kPa), fibrosis (F1-F2: LSM 7.3-12.4 kPa), and significant fibrosis (F3-F4: LSM>12.4 kPa). Demographic data (age, gender) and laboratory indicators (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, alkaline phosphatase, alpha-fetoprotein, platelet count) were collected to calculate the fibrosis-4 index (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI). Serum LMWK-Fc and α-Gal antibodies were measured and compared across the groups, and their correlation with fibrosis severity was analyzed. The receiver operating characteristic (ROC) curve was used to assess the predictive value of serum LMWK-Fc and α-Gal antibody levels for hepatic fibrosis. RESULTS: Among the 160 patients without complete liver biopsy, serum α-Gal antibody and LMWK-Fc levels increased progressively from the no fibrosis group to the significant fibrosis group, with statistically significant differences (P<0.05). Among the 115 patients with liver biopsy, serum LMWK-Fc levels were significantly higher in the fibrosis group and the significant fibrosis groups compared with the no fibrosis group, and α-Gal antibody levels were significantly higher in the significant fibrosis group compared with the no fibrosis group and the fibrosis group (P<0.001, P=0.032, respectively). Univariate and multivariate linear regression analyses showed that hepatic fibrosis was correlated with gender and LMWK-Fc levels (both P<0.05), but not with age, α-Gal antibody levels, FIB-4, or APRI (all P>0.05). CONCLUSIONS: The expression levels of serum LMWK-Fc and α-Gal antibodies vary across different stages of hepatic fibrosis, suggesting a potential association with fibrosis progression. LMWK-Fc levels have a certain predictive value for the diagnosis of hepatic fibrosis.
Assuntos
Cirrose Hepática , Humanos , Estudos Retrospectivos , Fígado/patologia , Feminino , Masculino , Fucose/metabolismo , Galactose , Pessoa de Meia-Idade , Adulto , Valor Preditivo dos Testes , Anticorpos/sangue , CininogêniosRESUMO
PURPOSE: To explore the incidence of antibodies against adalimumab (AAA) development in noninfectious uveitis (NIU) and to examine the impact of treatment adjustment in nonresponders. DESIGN: Retrospective case series. METHODS: In this single-center study of patients with NIU treated with adalimumab, blood samples for adalimumab and AAA were collected and therapeutic adjustments post-monitoring in non-responders were analyzed including changes in injection intervals, addition of conventional disease-modifying antirheumatic drugs (cDMARD), and treatment alterations to biologic DMARD. The main outcome measures were the proportion of patients with positive AAA and active uveitis, decrease of AAA at final follow-up by different therapeutic interventions. RESULTS: Of 42 patients who underwent laboratory investigations at 17.9 months after adalimumab initiation, 22 (52.4%) patients who were nonresponders demonstrated AAA (1243 ng/mL) with a mean adalimumab trough level of 3.0 µg/mL, significantly lower than the mean drug levels of patients without AAA (11.8 µg/mL). Fifteen (35.7%) patients were receiving concurrent treatment with a second immunosuppressive agent, but the mean antibody level and the mean adalimumab level were not statistically significantly different from the monotherapy group (P = .13 and P = .34). Reduction in AAA levels and relapse management was greatest among nonresponders who were treated by increasing the adalimumab dose and adding an additional immunosuppressive drug (-3565 ng/mL), followed by patients who were shifted to a different biologic (-1153 ug/mL). CONCLUSIONS: The presence of AAA was detected in 88% of nonresponder patients and was associated with undetectable adalimumab drug levels. This underscores immunogenicity as a major cause of loss of response in uveitis patients receiving biotherapies. Increasing the dose of adalimumab injections together with the addition of low-dose cDMARDs was the most effective adjustment in immunized nonresponders for whom the adalimumab drug concentration was low.
Assuntos
Adalimumab , Monitoramento de Medicamentos , Uveíte , Humanos , Adalimumab/uso terapêutico , Adalimumab/imunologia , Estudos Retrospectivos , Masculino , Feminino , Uveíte/tratamento farmacológico , Uveíte/imunologia , Pessoa de Meia-Idade , Adulto , Monitoramento de Medicamentos/métodos , Antirreumáticos/uso terapêutico , Anticorpos/sangue , Seguimentos , Idoso , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemRESUMO
BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse event identified following vaccination with some adenovirus-vectored COVID-19 vaccines, including Ad26.COV2.S. VITT is characterized by the presence of antibodies against platelet factor 4 (PF4). OBJECTIVES: To evaluate whether PF4 antibodies were generally induced following vaccination with adenovirus type 26 (Ad26)-vectored vaccines. METHODS: The study included 913 and 991 healthy participants without thromboembolic (TE) events in Ad26.COV2.S and non-COVID-19 Ad26-vectored vaccine clinical studies, respectively, and 1 participant with VITT following Ad26.COV2.S vaccination. PF4 antibody levels were measured in prevaccination and postvaccination sera. PF4 antibody positivity rates were assessed in a case-control setting in participants who developed TE events during participation in Ad26-vectored vaccine clinical studies. RESULTS: In the 1 VITT patient, PF4 antibodies were negative before vaccination. Seroconversion for platelet-activating PF4 antibodies was observed upon Ad26.COV2.S vaccination. In participants without TE events, the PF4 antibody levels and positivity rates were similar before and after Ad26 vaccination. Ad26 vaccination did not increase PF4 antibody levels in participants who were PF4 antibody-positive at baseline (n = 47). Lastly, 1 out of 28 TE cases and 2 out of 156 non-TE controls seroconverted after Ad26.COV2.S vaccination. None of the 15 TE cases and 3 of the 77 non-TE controls seroconverted following non-COVID-19 Ad26 vaccination. CONCLUSION: Ad26.COV2.S and the other Ad26-vectored vaccines studied did not generally induce PF4 antibodies or increase preexisting PF4 antibody levels. Moreover, unlike VITT, TE events that occurred at any time following Ad26 vaccination were not associated with PF4 antibodies.
Assuntos
Ad26COVS1 , Vacinas contra COVID-19 , Fator Plaquetário 4 , Vacinação , Humanos , Fator Plaquetário 4/imunologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Vacinação/efeitos adversos , Ad26COVS1/imunologia , Ad26COVS1/efeitos adversos , Estudos de Casos e Controles , Adulto Jovem , COVID-19/prevenção & controle , COVID-19/imunologia , Idoso , Adenoviridae/imunologia , Adenoviridae/genética , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/sangue , Anticorpos/sangue , Anticorpos/imunologia , AdolescenteRESUMO
INTRODUCTION: This study aimed to identify the blood transfusion rates for several surgical procedures in a single district general hospital and assess the value of preoperative blood type and antibody screen across all relevant surgical procedures. We hypothesized that there was an overuse of blood type and antibody screen in our general surgical population. METHODS: A database containing transfusions of patients who underwent elective- or emergency surgery from January 2015 to September 2020 was matched to a database of preoperative type-and-screen performed in the same period. Registered procedures where the incidence of transfusion is deemed low were excluded. The included procedures were assessed for the intraoperative usefulness of type- and-screen testing. RESULTS: In the included 68.892 surgeries, 36.134 (52.0%) blood samples were preoperatively tested for the blood type and screened for antibodies according to the hospital's routine. Overall 3.517 (5.1%) of surgeries had patients that received a transfusion in the perioperative period and 1.2% (n = 850) during the surgery. CONCLUSION: Most surgeries had a very low incidence of transfusion. Despite this, type-and-screen tests were widely used. This suggests the need for a more focused pre-surgery type-and-screen approach, and a more data driven approach to local guidelines in collaboration with surgical specialties.
Assuntos
Tipagem e Reações Cruzadas Sanguíneas , Transfusão de Sangue , Cuidados Pré-Operatórios , Humanos , Estudos Retrospectivos , Noruega , Transfusão de Sangue/estatística & dados numéricos , Masculino , Feminino , Cuidados Pré-Operatórios/métodos , Pessoa de Meia-Idade , Idoso , Anticorpos/sangue , Adulto , Antígenos de Grupos Sanguíneos/imunologiaRESUMO
OBJECTIVE: Comparing the utility of the anti-human serum amyloid A (SAA)-specific monoclonal and polyclonal antibodies assays (LZ-SAA) with the pure monoclonal anti-human antibody assays (VET-SAA) during clinical practice in primary care hospital populations by measuring SAA measurement in healthy and diseased domestic cats. ANIMALS: 52 healthy and 185 diseased client-owned cats. METHODS: SAA concentration was measured using different LZ-SAA and VET-SAA measurements for healthy and various diseased cats. Sensitivity, specificity, and accuracy were calculated for each disease. RESULTS: VET-SAA has higher sensitivity than LZ-SAA for the most common diseases presenting to primary care veterinary hospitals, including chronic kidney disease, tumors, and gingivostomatitis. Our results reveal the capability of detecting low SAA concentrations in healthy and diseased cats using VET-SAA in contrast to LZ-SAA, which found elevations of SAA concentrations only in diseased cats. CLINICAL RELEVANCE: Our findings indicate that switching to the new VET-SAA instead of the conventional LZ-SAA will likely enhance the diagnostic performance in primary care veterinary hospitals.
Assuntos
Anticorpos Monoclonais , Doenças do Gato , Hospitais Veterinários , Proteína Amiloide A Sérica , Animais , Gatos , Proteína Amiloide A Sérica/análise , Doenças do Gato/diagnóstico , Doenças do Gato/sangue , Doenças do Gato/imunologia , Anticorpos Monoclonais/imunologia , Sensibilidade e Especificidade , Imunoturbidimetria/métodos , Imunoturbidimetria/veterinária , Feminino , Imunoensaio/veterinária , Imunoensaio/métodos , Anticorpos/sangue , Anticorpos/imunologia , MasculinoRESUMO
To evaluate tumour necrosis factor inhibitor (TNFi) drug-levels and presence of anti-drug antibodies (ADAb) in patients with inflammatory arthritis who taper TNFi compared to TNFi continuation. Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis on stable TNFi dose and in low disease activity ≥ 12 months were randomised (2:1) to disease activity-guided tapering or control. Blood samples at baseline, 12- and 18-months were evaluated for TNFi drug-levels and ADAb. In total, 129 patients were randomised to tapering (n = 88) or control (n = 41). Between baseline and month 18, a significant shift in TNFi drug-levels were observed in the tapering group resulting in fewer patients with high drug-levels (change: - 14% [95% CI - 27 to - 1%]) and more with low drug-levels (change: 18% [95% CI 5-31%]). Disease activity was equivalent between groups at 18 months, mean difference: RA - 0.06 (95% CI - 0.44 to 0.33), PsA 0.03 (95% CI - 0.36 to 0.42), and axSpA 0.16 (- 0.17 to 0.49), equivalence margins ± 0.5 disease activity points. ADAb were detected in eight patients, all from the tapering group. TNFi drug-level category or ADAb were not predictive for achieving successful tapering at 18 months. TNFi drug-levels decreased during tapering which indicate adherence to the tapering algorithm. Despite the difference in TNFi drug-levels at 18 months, disease activity remained equivalent, and only few tapering patients had detectable ADAb. These data do not support using TNFi drug-level and/or ADAb to guide the tapering decision but future research with larger trials is needed.Trial registration: EudraCT: 2017-001970-41, December 21, 2017.
Assuntos
Antirreumáticos , Artrite Psoriásica , Artrite Reumatoide , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/sangue , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/imunologia , Artrite Psoriásica/sangue , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Redução da Medicação , Resultado do Tratamento , Espondilartrite/tratamento farmacológico , Espondilartrite/imunologia , Espondilartrite/sangue , Anticorpos/sangue , Idoso , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Formation of anti-drug antibodies (ADAs) against biologics is an important cause of psoriasis treatment failure. OBJECTIVE: This study aimed to summarize the characteristics of ADAs formation under different biological therapies and the influence of ADAs on the clinical effects and safety of biologics in patients with psoriasis. METHODS: PubMed, Embase, and Web of Science databases were searched from their inception to August 2022. Studies on biologics that assessed ADA levels in patients with psoriasis were included. The Cochrane risk-of-bias tool was used to assess the quality of randomized controlled trials (RCTs), the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control and cohort studies, and the Joanna Briggs Institute (JBI) critical appraisal checklist for single-arm studies. We calculated the pooled incidence with a random-effects model using R software. Subgroup analyses revealed that differences in patient characteristics, disease conditions, study design, and immunoassays may influence ADA generation and detection. RESULTS: The analysis included 86 studies, with a total population of 42,280 individuals. The pooled ADA rates were 0.49%, 2.20%, 2.38%, 4.08%, 7.38%, 7.94%, 14.29%, 21.93%, 29.70%, 31.76%, and 39.58% for secukinumab, etanercept, brodalumab, ustekinumab, tildrakizumab, guselkumab, ixekizumab, risankizumab, infliximab, adalimumab, and bimekizumab, respectively. >70% (95% CI, 0.71-0.81) of ADAs against adalimumab were neutralizing antibodies, and over 70% of ADAs against secukinumab and brodalumab were transient. Concomitant methotrexate therapy with tumor necrosis factor-α (TNF-α) inhibitors decreased ADA levels. Lower infliximab doses and intermittent therapy with interleukin (IL)-23 p19 inhibitors increased ADA formation. Additionally, ADA formation under treatment using TNF-α inhibitors and IL-12/23 p40 inhibitors was associated with lower response rates or serum drug levels, but only high ADA titers reduced the clinical effects of IL-17 inhibitors. The occurrence of IL-23 p19 and TNF-α inhibitors has been linked to injection-site reactions. CONCLUSIONS: Among the 11 biologics, secukinumab, etanercept, and brodalumab resulted in the lowest ADA formation rates. Immunogenicity contributes to lower biological efficacy and a higher likelihood of injection-site reactions. Low doses, intermittent treatment may increase ADA formation. An appropriate biologic should be selected based on the ADA formation rate and course of treatment.