RESUMEN
BACKGROUND: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. METHODS: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. RESULTS: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. CONCLUSIONS: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.
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Antígeno CTLA-4 , Interleucina-23 , Animales , Ratones , Humanos , Antígeno CTLA-4/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Interleucina-23/metabolismo , Femenino , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Modelos Animales de Enfermedad , Melanoma/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Masculino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios RetrospectivosRESUMEN
IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.
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Enfermedades Inflamatorias del Intestino , Interleucina-12 , Interleucina-23 , Inhibidores de las Cinasas Janus , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Inhibidores de las Cinasas Janus/uso terapéutico , Interleucina-23/antagonistas & inhibidores , Interleucina-23/metabolismo , Interleucina-23/inmunología , Interleucina-12/antagonistas & inhibidores , Interleucina-12/metabolismo , Interleucina-12/inmunología , Animales , Transducción de Señal/efectos de los fármacosRESUMEN
Psoriasis is a chronic inflammatory disease that sometimes necessitates therapeutic intervention with biologics. Autoantibody production during treatment with tumor necrosis factor (TNF) inhibitors is a recognized phenomenon, however, the production of autoantibodies associated with antiphospholipid syndrome (APS) has not been comprehensively evaluated in patients with psoriasis. This study was conducted to assess the prevalence of APS-associated autoantibodies in patients with psoriasis treated with different biologics and to investigate the potential associations between autoantibody production and clinical or serological parameters. Patients with psoriasis undergoing biologics treatments were enrolled in this study, and were categorized based on the type of biologics administered, TNF, interleukin (IL)-17, or IL-23 inhibitors. Clinical and serological data were collected and analyzed in conjunction with data on APS autoantibodies. TNF inhibitors were associated with a higher frequency of APS autoantibodies compared to IL-17 and IL-23 inhibitors. Notably, the presence of APS autoantibodies correlated with concurrent arthritis and higher disease severity at treatment initiation in patients treated with TNF inhibitors. Elevated Psoriasis Area and Severity Index scores and anti-nuclear antibody titers higher than × 320 were predictors of APS autoantibody production. Despite the higher autoantibody rates, clinical symptoms of APS were absent in these patients. This study provides the first comprehensive evidence of an increased frequency of APS autoantibodies associated with TNF inhibitor treatment in patients with psoriasis. The observed association between APS autoantibody positivity and TNF inhibitor treatment or clinical parameters suggests a potential immunomodulatory interplay between autoimmunity and inflammation in the pathogenesis of psoriasis.
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Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido , Productos Biológicos , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Femenino , Masculino , Persona de Mediana Edad , Productos Biológicos/uso terapéutico , Productos Biológicos/efectos adversos , Adulto , Anticuerpos Antifosfolípidos/sangre , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/tratamiento farmacológico , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-23/inmunología , Interleucina-23/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Prevalencia , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Índice de Severidad de la Enfermedad , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
BACKGROUND: To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. METHOD: We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/µL) or grade 3 (neutrophil count < 1,000/µL) neutropenia. RESULTS: Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia. CONCLUSION: No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.
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Adalimumab , Interleucina-17 , Interleucina-23 , Neutropenia , Psoriasis , Talidomida , Humanos , Adalimumab/efectos adversos , Adalimumab/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Femenino , Masculino , Neutropenia/inducido químicamente , Neutropenia/inmunología , Neutropenia/epidemiología , Persona de Mediana Edad , Japón , Adulto , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-23/antagonistas & inhibidores , Interleucina-23/inmunología , Talidomida/efectos adversos , Talidomida/análogos & derivados , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversosRESUMEN
Psoriatic arthritis (PsA) is part of the psoriatic disease spectrum and is characterized by a chronic inflammatory process that affects entheses, tendons and joints. Cytokines produced by immune and non-immune cells play a central role in the pathogenesis of PsA by orchestrating key aspects of the inflammatory response. Pro-inflammatory cytokines such as TNF, IL-23 and IL-17 have been shown to regulate the initiation and progression of PsA, ultimately leading to the destruction of the architecture of the local tissues such as soft tissue, cartilage and bone. The important role of cytokines in PsA has been underscored by the clinical success of antibodies that neutralize their function. In addition to biologic agents targeting individual pro-inflammatory cytokines, signaling inhibitors that block multiple cytokines simultaneously such as JAK inhibitors have been approved for PsA therapy. In this review, we will focus on our current understanding of the role of cytokines in the disease process of PsA and discuss potential new treatment options based on modulation of cytokine function.
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Artritis Psoriásica , Citocinas , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/inmunología , Humanos , Citocinas/inmunología , Animales , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-23/inmunología , Interleucina-23/antagonistas & inhibidores , Transducción de Señal , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Inhibidores de las Cinasas Janus/uso terapéuticoRESUMEN
Pityriasis rubra pilaris (PRP) is a rare and chronic inflammatory dermatologic condition characterized by hyperkeratotic salmon-colored plaques and palmoplantar keratoderma. Traditional therapeutic modalities have shown limited efficacy and often entail potential adverse effects, highlighting the need for alternative treatment options. Our review aims to summarize the current evidence on the off-label use of IL-23 inhibitors, risankizumab and guselkumab, in the treatment of PRP. These biologic agents have been approved for psoriasis, and their potential role in managing PRP has recently garnered interest. We conducted a comprehensive literature search on PubMed and Scopus databases, identifying relevant studies published in English up to June 2023 following PRISMA guidelines. A total of 10 studies were selected for data extraction and review. Results from the selected studies demonstrated encouraging outcomes with both risankizumab and guselkumab in managing PRP. Among 11 patients treated with risankizumab, 10 showed notable improvements in various disease manifestations, including pruritus, erythema, and affected body surface area. DLQI scores and BSA percentages reported a significant improvement before and after risankizumab treatment (p = 0.0322; p = 0.0216). However, two cases also reported symptom aggravation or even disease worsening. Patients treated with guselkumab exhibited ultimate improvement in all five cases, with complete clearance in three out of five cases. DLQI and BSA percentages also reported significant improvement with treatment with guselkumab (p = 0.0172; p < 0.0001). While most cases demonstrated positive outcomes, there were isolated instances of worsening symptoms, emphasizing the need for caution and further investigation. Further research with larger sample sizes and longer follow-up periods is necessary to establish the efficacy, optimal dosing, and long-term safety of risankizumab and guselkumab in treating PRP. Overall, we provide valuable insights into the potential use of IL-23 inhibitors, risankizumab, and guselkumab, as promising treatment options for PRP. These biologics have shown efficacy in improving symptoms in treatment-resistant cases, offering new avenues for clinicians to explore in the treatment of PRP.
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Anticuerpos Monoclonales Humanizados , Pitiriasis Rubra Pilaris , Humanos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/efectos adversos , Interleucina-23/antagonistas & inhibidores , Interleucina-23/inmunología , Uso Fuera de lo Indicado , Pitiriasis Rubra Pilaris/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.
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Colitis , Interleucina-17 , Células Th17 , Animales , Administración Oral , Ratones , Humanos , Ratas , Colitis/tratamiento farmacológico , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inhibidores , Células Th17/inmunología , Receptores de Interleucina/metabolismo , Receptores de Interleucina/antagonistas & inhibidores , Ratones Endogámicos C57BL , Masculino , Interleucina-23/metabolismo , Interleucina-23/antagonistas & inhibidores , Distribución Tisular , Femenino , Ratas Sprague-DawleyRESUMEN
Objective: Treatment options with disease-modifying antirheumatic drugs (DMARDs) for psoriatic arthritis (PsA) have evolved over recent years. In addition to Janus kinase inhibitors (JAKi), four classes of biologic DMARDs (bDMARDs; interleukin [IL]-23 inhibitors [IL-23i], IL-12/23 inhibitors [IL-12/23i], tumor necrosis factor inhibitors [TNFi], and IL-17 inhibitors [IL-17i]) are currently approved for moderate to severe PsA treatment. There is minimal evidence of the persistence of these drugs among PsA outpatients in a real-world scenario during the period following the approval of JAKi. Therefore, we aimed to analyze the drug survival rates of biologic and JAKi therapies among German PsA outpatients during routine clinical care. Methods: We retrospectively analyzed PsA patients with a new prescription for a biologic or JAKi in the RHADAR database between January 2015 and October 2023. Kaplan-Meier Curves and Cox regression modelling were used to compare drug survival rates. Results: 1352 new prescriptions with bDMARDs (IL-12/23i [n=50], IL-23i [n=31], TNFi [n=774], IL-17i [n=360]) or JAKi (n=137) were identified. The 5-year drug survival rate was 67.8% for IL-17i, 62.3% for TNFi, 53.3% for JAKi, and 46.0% for IL-12/23i. Discontinuation probabilities for JAKi and IL-12/23i were significantly higher compared with TNFi (JAKi hazard ratio [HR] 1.66, [95% CI 1.23-2.24], p=0.001; IL-12/23i HR 1.54, [95% CI 1.02-2.33], p=0.042) and IL-17i (JAKi HR 1.77, [95% CI 1.27-2.47], p=0.001; IL-12/23i HR 1.64, [95% CI 1.06-2.55], p=0.027). JAKi-treated patients had more severe disease and more osteoarthritis (OA) compared to TNFi and more OA compared to IL-17i. Conclusion: German PsA outpatients might persist longer with TNFi and IL-17i compared with IL-12/23i or JAKi. For TNFi, differences in subgroup characteristics and comorbidities (OA) may have affected drug survival rates. For IL-17i, the longer drug survival might not only be related to less OA compared to JAKi and, therefore, might be affected by other factors.
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Antirreumáticos , Artritis Psoriásica , Interleucina-12 , Interleucina-17 , Interleucina-23 , Inhibidores de las Cinasas Janus , Humanos , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/mortalidad , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Interleucina-17/antagonistas & inhibidores , Alemania , Interleucina-12/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/uso terapéutico , Antirreumáticos/uso terapéutico , Adulto , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Anciano , Bases de Datos Factuales , Pacientes Ambulatorios , Resultado del TratamientoRESUMEN
Interleukin (IL)-23 inhibitor monoclonal antibodies shown significant efficacy in treating autoimmune diseases. DNA or RNA aptamers exhibit comparable specificity to antibodies, are cost-effective, non-immunogenic, and do not have batch to batch variation. This study aimed to characterize a single-stranded DNA (ssDNA) aptamer targeting human IL-23. The alpha subunit of IL-23 (P19) and intact IL-23 were cloned, expressed, and the proteins finally were purified through Ni2+-iminodiacetic acid affinity chromatography. The selection and characterization of ssDNA aptamer against P19 were conducted using the protein-systematic evolution of ligands by exponential enrichment (SELEX). Dot blot assay was carried out to monitor binding of the aptamer output of SELEX rounds, to P19 protein. The dissociation constant (Kd) of aptamers with positive results in dot blot assay, determined based on their binding to IL-23 using an ELISA method. Recombinant P19 and IL-23 proteins were 26 and 72â¯kDa, respectively, observed on SDS-PAGE .12â¯%. The aptamers output from 7, 8, 9, 10, 11, and 12 rounds of the SELEX was monitored by dot blot assay, revealing that the aptamer from the round 8 has stronger luminescent signal and was selected for TA-cloning. After analyzing the biotinylated aptamers from clones, positive clones in dot blot assay and ELISA were sequenced. Finally, the Kd calculation revealed three aptamers with high affinity, named A23P3, A23P6, and A23P15 with Kd values of 1.37, 2.139, and 2.88â¯nM, respectively. Results of this study introduced three specific anti-IL-23 ssDNA aptamers with high affinity, which could be utilized for therapeutic and diagnostic purposes.
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Aptámeros de Nucleótidos , ADN de Cadena Simple , Técnica SELEX de Producción de Aptámeros , Aptámeros de Nucleótidos/química , Técnica SELEX de Producción de Aptámeros/métodos , Humanos , Interleucina-23/antagonistas & inhibidores , Proteínas Recombinantes , Subunidad p19 de la Interleucina-23/antagonistas & inhibidores , Cromatografía de Afinidad/métodosAsunto(s)
Fármacos Dermatológicos , Sustitución de Medicamentos , Interleucina-23 , Psoriasis , Ustekinumab , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Ustekinumab/uso terapéutico , Interleucina-23/antagonistas & inhibidores , Interleucina-23/inmunología , Resultado del Tratamiento , Femenino , Masculino , Fármacos Dermatológicos/uso terapéutico , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Índice de Severidad de la Enfermedad , Estudios Retrospectivos , Adalimumab/uso terapéuticoRESUMEN
The pathogenesis of psoriasis has been linked to autoimmune and autoinflammatory traits that result in atypical cytokine and keratinocyte activation and proliferation. Many cytokine pathways are involved in the development of inflammation with interleukin-23 (IL-23) playing a significant role in plaque-type psoriasis. Biologic agents that target specific cytokines have shown to be effective therapies in the treatment of plaque-type psoriasis over other conventional treatments such as systemic retinoids. Tildrakizumab is an immunoglobulin G1-kappa monoclonal antibody that inhibits the IL-23/IL-17 pathway and has demonstrated through two three-part randomized Phase 3 clinical trials (reSURFACE 1 and reSURFACE 2) and their extension trials to be an efficacious and safe therapy for the targeted treatment of moderate-to-severe plaque-type psoriasis.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Interleucina-23/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Interleucina-17/antagonistas & inhibidores , Resultado del Tratamiento , Ensayos Clínicos Fase III como AsuntoRESUMEN
Significant research advances in our understanding of psoriatic disease have led to the development of several highly selective, effective, and safe topical and systemic treatments. These treatments have led to unprecedented levels of disease clearance and control for most patients with psoriasis with cutaneous disease. However, there remains a need for improved treatments for those patients with recalcitrant disease, psoriatic arthritis, or nonplaque disease variants. Recently approved therapies and investigational products in ongoing clinical development programs that target IL-17A/F, IL-23, TYK2, PDE4, AhR or IL-36 cytokine signaling are improving the clinician's ability to care for a broader range of patients affected by psoriasis.
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Fármacos Dermatológicos , Inhibidores de Fosfodiesterasa 4 , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-23/antagonistas & inhibidores , Ustekinumab/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Interleucina-17/antagonistas & inhibidores , Artritis Psoriásica/tratamiento farmacológico , TYK2 Quinasa/antagonistas & inhibidores , Talidomida/análogos & derivadosRESUMEN
Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Productos Biológicos , Psoriasis , Ustekinumab , Psoriasis/tratamiento farmacológico , Humanos , Productos Biológicos/uso terapéutico , Ustekinumab/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Etanercept/uso terapéutico , Adalimumab/uso terapéutico , Infliximab/uso terapéutico , Interleucina-17/antagonistas & inhibidores , Fármacos Dermatológicos/uso terapéutico , Certolizumab Pegol/uso terapéutico , Interleucina-23/antagonistas & inhibidores , Interleucina-12/antagonistas & inhibidoresRESUMEN
Importance: There is no US Food and Drug Administration-approved treatment for pityriasis rubra pilaris (PRP), and it is common for patients to fail to experience improvement with several systemic options. Involvement of interleukin (IL) 23 suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for participants with PRP and better understand gene and protein dysregulation in PRP. Design, Setting, and Participants: This single-arm, investigator-initiated nonrandomized trial was conducted from October 2019 to August 2022 at a single-center academic university with participants from 8 states in the US. In total, 14 adults with moderate to severe PRP were enrolled; 12 completed the trial. Age-matched and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. The primary outcome was observed at 24 weeks, and additional follow-up occurred at 36 weeks. Intervention: Guselkumab is a fully human immunoglobulin G1 λ monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23. Subcutaneous injections were given at the US Food and Drug Administration-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was the mean change in the Psoriasis Area Severity Index (PASI) score at week 24. Secondary outcomes included pruritus, Dermatology Life Quality Index score, clinical response at week 36, and association with transcriptomics and proteomics expression. Results: A per-protocol analysis was performed for the cohort of 4 female and 8 male patients who had a mean (SD) age of 56.5 (18.7) years. The mean improvement in PASI score, pruritus, and Dermatology Life Quality Index score was 61.8% (P < .001), 62.3% (P = .001), and 60.2% (P < .001), respectively. Nine participants (75%) achieved a 50% improvement in PASI. Among these clinical responders, at week 36, 8 of 9 achieved PASI75, and 6 of 9 achieved PASI90. No participants had pathogenic CARD14 gene variations. There was 1 serious adverse event that was not associated with the study drug. Proteomics and gene expression profiles identified dysregulation of a predominance of inflammatory pathways (such as T helper 17 and nuclear factor κ B) in participants with PRP who later responded well to treatment with guselkumab and stronger dysregulation of keratinocyte development pathways in individuals who did not respond to guselkumab. Conclusion and Relevance: The results of this nonrandomized trial suggest that guselkumab has efficacy in treating refractory moderate to severe adult PRP. Trial Registration: ClinicalTrials.gov Identifier: NCT03975153.
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Anticuerpos Monoclonales Humanizados , Interleucina-17 , Pitiriasis Rubra Pilaris , Transducción de Señal , Humanos , Pitiriasis Rubra Pilaris/tratamiento farmacológico , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Persona de Mediana Edad , Adulto , Interleucina-17/antagonistas & inhibidores , Interleucina-17/metabolismo , Transducción de Señal/efectos de los fármacos , Índice de Severidad de la Enfermedad , Interleucina-23/antagonistas & inhibidores , Resultado del Tratamiento , Subunidad p19 de la Interleucina-23/antagonistas & inhibidores , Anciano , Inyecciones Subcutáneas , Guanilato Ciclasa/metabolismo , Proteínas de la Membrana , Proteínas Adaptadoras de Señalización CARDRESUMEN
BACKGROUND AND OBJECTIVE: The most recently approved biologics for moderate-to-severe psoriasis are the interleukin (IL)-17 and IL-23 inhibitors. Drug survival is a frequently used outcome to assess drug performance in practice. An overview of the available drug survival studies regarding IL-17 and IL-23 inhibitors is lacking. Therefore, our objective was to assess the drug survival of IL-17 and IL-23 inhibitors for psoriasis. METHODS: A search of PubMed, Embase, Cochrane Library and Web of Science was conducted (last search 27 December, 2023). Inclusion criteria were (1) cohort study; (2) patients aged ≥ 18 years with plaque psoriasis; and (3) evaluation of drug survival of at least one of the IL-17 and IL-23 inhibitors. Exclusion criteria were: primary focus on patients with psoriatic arthritis, fewer than ten study subjects and another language than English. The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Survival probabilities at monthly intervals were extracted from Kaplan-Meier curves using a semi-automated tool. Data were pooled using a non-parametric random-effects model to retrieve distribution-free summary survival curves. Summary drug survival curves were constructed per biologic for different discontinuation reasons: overall, ineffectiveness and adverse events, and split for the effect modifier biologic naivety. Results were analysed separately for registry/electronic health record data and for pharmacy/claims data. RESULTS: A total of 69 studies aggregating drug survival outcomes of 48,704 patients on secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, and tildrakizumab were included. Summary drug survival estimates of registry/electronic health record studies for overall, ineffectiveness and adverse event related drug survival were high (all point estimates ≥ 0.8 at year 1) for included biologics, with highest estimates for guselkumab and risankizumab. All estimates for drug survival were higher in biologic naive than in experienced patients. Estimates of pharmacy/claims databases were substantially lower than estimates from the primary analyses based on registry/electronic health record data. CONCLUSIONS: This meta-analysis showed that the investigated IL-17 and IL-23 inhibitors had high drug survival rates, with highest rates for guselkumab and risankizumab drug survival. We showed that effect modifiers such as biologic naivety, and the source of data used (registry/electronic health record data vs pharmacy/claims databases) is relevant when interpreting drug survival studies.
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Interleucina-17 , Interleucina-23 , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Interleucina-17/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/farmacología , Fármacos Dermatológicos/efectos adversosRESUMEN
Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.
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Interleucina-23 , Animales , Humanos , Artritis Psoriásica/inmunología , Artritis Psoriásica/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/terapia , Interleucina-23/antagonistas & inhibidores , Interleucina-23/inmunología , Interleucina-23/metabolismo , Psoriasis/inmunología , Psoriasis/tratamiento farmacológico , Transducción de SeñalRESUMEN
Cytokines produced by immune cells contribute to the development and perpetuation of inflammatory bowel disease (IBD), namely Crohn's disease and ulcerative colitis, by regulating various aspects of the inflammatory response. Pro-inflammatory cytokines trigger chronic intestinal inflammation, tissue damage, carcinogenesis and perpetuation of disease and suppress the resolution of inflammation in IBD. The clinical success of antibodies that neutralize tumour necrosis factor (TNF) and the cytokine IL-12p40 in individuals with IBD has underscored this concept. Moreover, genetic and preclinical studies have emphasized the crucial role of IL-23 in IBD, leading to clinical approval of antibodies targeting this cytokine. Multiple studies have also investigated the administration of cytokines with assumed anti-inflammatory effects, but this approach has yet to show any real clinical benefit in individuals with IBD. Recent studies have targeted the cytokine network through the use of multi-cytokine blockers (for example, Janus kinase (JAK) inhibitors), IL-2-induced regulatory T cells or advanced combination therapies that use multiple cytokine blockers simultaneously (for example, anti-TNF along with anti-IL-23 antibodies). This Review will focus on our current understanding of how cytokines produced by innate and adaptive immune cells contribute to IBD pathogenesis and discuss how their modulation may inform future treatments for IBD.
Asunto(s)
Citocinas , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Citocinas/inmunología , Citocinas/metabolismo , Animales , Linfocitos T Reguladores/inmunología , Interleucina-23/inmunología , Interleucina-23/antagonistas & inhibidores , Interleucina-23/metabolismo , Inmunidad Innata/inmunologíaRESUMEN
BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).