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INTRODUCTION: Consensus is lacking regarding the number of eosinophils (eos) required for the diagnosis of eosinophilic gastritis (EoG) and eosinophilic duodenitis (EoD). In addition, thresholds that require multiple high-power fields (HPFs) may not be practical for clinical use, resulting in delayed or missed diagnoses. This pooled analysis of 4 prospective studies assessed thresholds for multiple and single HPFs used to diagnose EoG and EoD. METHODS: Studies included the phase 2 ENIGMA1, the phase 3 ENIGMA2, an EoG/EoD prevalence study and a healthy volunteer study. Eos were quantified in the epithelium and lamina propria for controls and symptomatic participants. Symptomatic participants were further divided by histologic diagnosis of EoG/EoD. Peak eos counts were assessed, and the area under the receiver operating characteristic curve was analyzed to identify eos cutoffs for detection of EoG/EoD using the Youden index and sensitivity and specificity equality approaches. RESULTS: Based on the highest specificity analysis in 740 patients, the optimal eos threshold was determined to be 20 eos/HPF in 5 gastric HPFs for EoG (71% sensitivity and 94% specificity) and 33 eos/HPF in 3 duodenal HPFs for EoD (49% sensitivity and 100% specificity). For single-field analysis, the optimal eos thresholds were 33 eos/HPF (EoG) and 37 eos/HPF (EoD), both corresponding to 93% sensitivity and 93% specificity. DISCUSSION: Highly specific single gastric and duodenal HPF thresholds may have more clinical applicability than thresholds requiring multiple HPFs and could better facilitate development of practical histopathologic guidelines to aid pathologists and clinicians in the detection and diagnosis of EoG and/or EoD.
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Duodenitis , Enteritis , Eosinofilia , Gastritis , Humanos , Eosinófilos/patología , Estudios Prospectivos , Duodenitis/diagnóstico , Duodenitis/patología , Eosinofilia/diagnósticoRESUMEN
BACKGROUND: Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation. OBJECTIVES: To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM. METHODS: At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03â mg kg-1; in part B, patients received one lirentelimab dose of 0.3â mg kg-1 or 1.0â mg kg-1; and in part C, patients received either 1.0â mg kg-1 lirentelimab every 4 weeks for 6â months or ascending doses of lirentelimab (one dose of 1â mg kg-1 followed by five doses of 3-10â mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose. RESULTS: In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51â years, 76% female, median 4.6â years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%). CONCLUSIONS: Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.
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Anticuerpos Monoclonales , Antineoplásicos , Mastocitosis Sistémica , Mastocitosis , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Mastocitos , Mastocitosis/diagnóstico , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/complicaciones , Calidad de VidaRESUMEN
The term "allergic diseases" encompasses several common, IgE-mediated conditions that range from being annoying to those that are life-threatening. Available treatments include active avoidance of the instigating allergen and the use of a variety of oral, inhaled, intranasal, intraocular and injected agents. While most individuals with allergies do well with existing therapies, there are still unmet therapeutic needs. Siglecs (sialic acid-binding, immunoglobulin-like lectins) are a family of single-pass transmembrane I-type lectins found on various subsets of cells, especially those of the immune system. All Siglecs have extracellular domains recognizing sialoside ligands, and most contain cytoplasmic domains with inhibitory signaling activity. This review focuses on Siglecs that likely play a role in regulating allergic and asthmatic responses, and how specific Siglecs, expressed on cells such as eosinophils and mast cells, are being targeted for therapeutic benefit.
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Asma , Hipersensibilidad , Humanos , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Antígenos CD , Transducción de Señal , Asma/terapiaRESUMEN
BACKGROUND: Allergic conjunctivitis (AC) is an ocular inflammatory disease with symptoms driven by eosinophils and mast cells. Allergic comorbidities are common. Current treatments are often ineffective in severe AC and limited by potential side effects. Lirentelimab is an anti-sialic acid-binding immunoglobulin-like lectin-8 mAb that depletes eosinophils and inhibits mast cells. OBJECTIVE: We sought to determine safety and preliminary efficacy of lirentelimab in an open-label, phase 1b study. METHODS: Patients with chronic, severely symptomatic atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC, and who had history of topical or systemic corticosteroid use, were enrolled to receive up to 6 monthly lirentelimab infusions (dose 1: 0.3 mg/kg, dose 2: 1 mg/kg, subsequent doses: 1 or 3 mg/kg). Changes from baseline in peripheral blood eosinophils, changes in patient-reported symptoms (measured by daily Allergic Conjunctivitis Symptom Questionnaire, including atopic comorbidities), changes in investigator-reported ocular signs and symptoms (Ocular Symptom Scores), changes in quality of life, and changes in tear cytokine and chemokine levels were assessed. RESULTS: Thirty patients were enrolled (atopic keratoconjunctivitis n = 13, vernal keratoconjunctivitis n = 1, perennial AC n = 16), 87% of whom had atopic comorbidities. After lirentelimab treatment, mean improvement was observed in Allergic Conjunctivitis Symptom Questionnaire score (-61%; 95% CI, -75% to -48%) and Ocular Symptom Scores (-53%; 95% CI, -76% to -31%), consistent across atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC groups. There was substantial improvement in atopic comorbidities, with -55% (95% CI, -78% to -31%), -50% (95% CI, -82% to -19%), and -63% (95% CI, -87% and -38%) reduction in symptoms of atopic dermatitis, asthma, and rhinitis, respectively. Levels of key mediators of inflammation were reduced in patient tears after lirentelimab treatment. The most common adverse effects were mild to moderate infusion-related reactions. CONCLUSIONS: Lirentelimab was well tolerated, improved severe AC and concomitant atopic symptoms, and reduced inflammatory mediators in patient tears.
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Antineoplásicos , Conjuntivitis Alérgica , Enfermedad Injerto contra Huésped , Queratoconjuntivitis , Antineoplásicos/efectos adversos , Conjuntivitis Alérgica/diagnóstico , Conjuntivitis Alérgica/tratamiento farmacológico , Ojo , Humanos , Calidad de Vida , LágrimasRESUMEN
BACKGROUND: Chronic urticaria (CU) is a debilitating mast cell-driven disease, often refractory to standard therapy (ie, antihistamines). Lirentelimab, an anti-sialic acid-binding immunoglobulin-like lectin 8 mAb, selectively inhibits mast cells and depletes eosinophils. OBJECTIVE: We sought to determine safety and efficacy of lirentelimab in patients with CU. METHODS: This phase 2a study enrolled patients with CU refractory to up to 4-fold H1-antihistamine doses. Patients received 6 monthly intravenous doses of lirentelimab (0.3, 1, and up to 3 mg/kg). Primary efficacy end point was change in Urticaria Control Test score at week 22. Urticaria Activity Score weekly average (UAS7) was assessed in patients with chronic spontaneous urticaria (CSU), and Cholinergic UAS7 was used for patients with cholinergic urticaria (CholU). RESULTS: A total of 45 patients were enrolled in 4 cohorts (n = 13 omalizumab-naive CSU, n = 11 omalizumab-refractory CSU, n = 11 CholU, n = 10 symptomatic dermographism). Urticaria Control Test scores increased with lirentelimab across cohorts, with mean changes at week 22 of 11.1 ± 4.1, 4.8 ± 7.0, 6.5 ± 6.2, and 3.4 ± 4.1 and complete response rates (Urticaria Control Test score ≥ 12) of 92%, 36%, 82%, and 40%, respectively. In omalizumab-naive and omalizumab-refractory patients with CSU, disease activity decreased at week 22 (mean UAS7 change, -73% and -47%, respectively), with UAS7 response rates (≥50% reduction) of 77% and 45%, respectively. In patients with symptomatic dermographism, 50% (5 of 10) and 40% (4 of 10) had complete itch and hive resolution by FricTest, respectively, and 100% (7 of 7) evaluable patients with CholU had negative responses to Pulse-Controlled Ergometry exercise test. Most common adverse events included infusion-related reactions (43%; all mild/moderate and transient), nasopharyngitis (21%), and headache (19%). No treatment-related serious adverse events occurred. CONCLUSIONS: Lirentelimab demonstrated activity across 3 forms of antihistamine-refractory CU.
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Antialérgicos , Antineoplásicos , Urticaria Crónica , Enfermedad Injerto contra Huésped , Urticaria , Anticuerpos Monoclonales/uso terapéutico , Colinérgicos/uso terapéutico , Enfermedad Crónica , Urticaria Crónica/tratamiento farmacológico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Omalizumab/efectos adversos , Prueba de Estudio Conceptual , Resultado del Tratamiento , Urticaria/inducido químicamente , Urticaria/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: Eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD), characterized by chronic gastrointestinal (GI) symptoms and increased numbers or activation of eosinophils and mast cells in the GI tract, are likely underdiagnosed. We aimed to determine rates of EG and EoD and number of biopsies required to optimize detection using screening data from a randomized trial of lirentelimab (AK002), an antibody against siglec-8 that depletes eosinophils and inhibits mast cells. We also characterized endoscopic features and symptoms of EG and EoD. METHODS: Subjects with moderate-to-severe GI symptoms, assessed daily through a validated patient-reported outcome questionnaire, underwent endoscopy with a systematic gastric and duodenal biopsy protocol and histopathologic evaluation. EG diagnosis required presence of ≥30 eosinophils/high-power field (eos/hpf) in ≥5 hpfs and EoD required ≥30 eos/hpf in ≥3 hpfs. We analyzed diagnostic yields for EG and EoD and histologic, endoscopic, and clinical findings. RESULTS: Of 88 subjects meeting symptom criteria, 72 were found to have EG and/or EoD (EG/EoD), including patients with no prior diagnosis of EG/EoD. We found that GI eosinophilia was patchy and that examination of multiple biopsies was required for diagnosis-an average of only 2.6 per 8 gastric biopsies and 2.2 per 4 duodenal biopsies per subject met thresholds for EG/EoD. Evaluation of multiple nonoverlapping hpfs in each of 8 gastric and 4 duodenal biopsies was required to capture 100% of EG/EoD cases. Neither endoscopic findings nor symptom severity correlated with eosinophil counts. CONCLUSIONS: In an analysis of patients with moderate-to-severe GI symptoms participating in a clinical trial of lirentelimab for EG/EoD, we found eosinophilia to be patchy in gastric and duodenal biopsies. Counting eosinophils in at least 8 gastric and 4 duodenal biopsies is required to identify patients with EG/EoD, so they can receive appropriate treatment. (ClinicalTrials.gov, Number: NCT03496571).
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Duodenitis , Enteritis , Eosinofilia , Esofagitis Eosinofílica , Biopsia , Duodenitis/diagnóstico , Duodenitis/patología , Enteritis/diagnóstico , Enteritis/tratamiento farmacológico , Eosinofilia/diagnóstico , Eosinofilia/tratamiento farmacológico , Esofagitis Eosinofílica/patología , Eosinófilos/patología , Gastritis , HumanosRESUMEN
Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.
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Anticuerpos Monoclonales Humanizados , Antígenos CD , Antígenos de Diferenciación de Linfocitos B , Eosinófilos/inmunología , Hipersensibilidad , Inflamación , Lectinas , Mastocitos/inmunología , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos CD/inmunología , Antígenos CD/fisiología , Antígenos de Diferenciación de Linfocitos B/inmunología , Antígenos de Diferenciación de Linfocitos B/fisiología , Ensayos Clínicos como Asunto , Eosinófilos/patología , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Lectinas/inmunología , Lectinas/fisiología , Mastocitos/patología , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis. METHODS: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score. RESULTS: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group). CONCLUSIONS: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.).
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Duodenitis/tratamiento farmacológico , Enteritis/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Eosinófilos , Gastritis/tratamiento farmacológico , Lectinas/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Duodenitis/complicaciones , Enteritis/complicaciones , Eosinofilia/complicaciones , Femenino , Gastritis/complicaciones , Tracto Gastrointestinal/inmunología , Humanos , Infusiones Intravenosas/efectos adversos , Lectinas/inmunología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Mast cells and eosinophils are innate immune cells involved in both acute and chronic inflammatory responses. Siglecs are a family of cell surface receptors that share sialic acid binding activity. Over the past 20 years, our knowledge of the expression and function of Siglecs on cells of the immune system and others has greatly expanded, as has our understanding of their signaling, ligands, and possible roles in disease pathophysiology. Because of this, Siglecs have garnered interest as potential drug targets using strategies ranging from biologics to ligand-directed nanoparticles. This mini-review will highlight the state of our knowledge regarding human eosinophil and mast cell Siglecs, their biology, what they recognize, tools developed for in vitro and preclinical experimentation, and the status of ongoing efforts to develop drugs that engage eosinophil and mast cell Siglecs for potential therapeutic benefit.