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1.
ERJ Open Res ; 10(1)2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38196889

RESUMEN

Background: The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab. Methods: In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups (post hoc). Mepolizumab-related OCS-sparing benefits were also quantified. Results: Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day-1. The proportion of patients with clinical benefit was greater with mepolizumab versus placebo (range 76-81% versus 25-39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumab versus placebo accrued significantly more weeks on OCS ≤4 mg·day-1 (OR 5.06, 95% CI 2.47-10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks. Conclusions: Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA.

2.
Mayo Clin Proc ; 98(7): 1054-1070, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37419574

RESUMEN

Elevated eosinophil counts are implicated in multiple diseases, from relatively prevalent organ-specific disorders such as severe eosinophilic asthma, to rare multisystem disorders such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA). Patients with these multisystem diseases, often associated with markedly elevated eosinophil counts, have a substantial risk of morbidity and mortality due to delayed diagnosis or inadequate treatment. A thorough workup of symptomatic patients presenting with elevated eosinophil counts is essential, although in some cases the differential diagnosis may remain difficult because of overlapping presentations between HES and EGPA. Notably, first- and second-line treatment options and response to therapy may differ for specific HES and EGPA variants. Oral corticosteroids are the first line of treatment for HES and EGPA, except when HES is the result of specific mutations driving clonal eosinophilia that are amenable to targeted treatment with a kinase inhibitor. Cytotoxic or immunomodulatory agents may be required for those with severe disease. Novel eosinophil-depleting therapies, such as those targeting interleukin 5 or its receptor, have shown great promise in reducing blood eosinophil counts, and reducing disease flares and relapses in patients with HES and EGPA. Such therapies could reduce the side effects associated with long-term oral corticosteroids or immunosuppressant use. This review provides a pragmatic guide to approaching the diagnosis and clinical management of patients with systemic hypereosinophilic disorders. We highlight practical considerations for clinicians and present cases from real-world clinical practice to show the complexity and challenges associated with diagnosing and treating patients with HES and EGPA.


Asunto(s)
Antineoplásicos , Asma , Síndrome de Churg-Strauss , Eosinofilia , Granulomatosis con Poliangitis , Humanos , Síndrome de Churg-Strauss/complicaciones , Granulomatosis con Poliangitis/complicaciones , Eosinofilia/complicaciones , Eosinófilos , Antineoplásicos/uso terapéutico , Corticoesteroides/uso terapéutico , Asma/diagnóstico
3.
ACR Open Rheumatol ; 5(7): 354-363, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37312233

RESUMEN

OBJECTIVE: To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype. METHODS: The MIRRA study (NCT02020889/GSK ID: 115921) included adults with relapsing/refractory EGPA and 4 or more weeks of stable oral glucocorticoids (OG). Patients received mepolizumab (300 mg subcutaneously every 4 weeks) or placebo, plus standard of care for 52 weeks. This post hoc analysis assessed EGPA vasculitic phenotype using antineutrophil cytoplasmic antibody (ANCA) history, baseline Birmingham Vasculitis Activity Score (BVAS), and Vasculitis Damage Index (VDI) score. Coprimary endpoints included accrued remission over 52 weeks and proportion in remission at Week 36 and Week 48. Remission was defined as a BVAS equal to 0 and an OG dose of 4 or more mg/day of a prednisone equivalent. Types of relapses (vasculitis, asthma, and sino-nasal) and EGPA vasculitic characteristics (by study remission status) were also assessed. RESULTS: A total of 136 patients were included (n = 68, mepolizumab and placebo). Irrespective of history of ANCA positivity status, baseline BVAS, or baseline VDI, the accrued remission duration and the proportion of patients in remission at Weeks 36 and 48 were greater with mepolizumab compared with placebo. With mepolizumab, remission at both Week 36 and Week 48 was achieved by 54% of patients with and 27% of patients without a history of ANCA positivity compared with 0% and 4%, respectively (placebo); 45% of patients with a BVAS of 0 and 22% of patients with BVAS of greater than 0 compared with 5% and 2%, respectively (placebo); and 29% of patients with a VDI score of less than 5 and 37% of patients with a VDI score of 5 or more compared with 6% and 0%, respectively (placebo). Mepolizumab reduced all types of relapses as compared with placebo. Baseline vasculitic characteristics (neuropathy, glomerulonephritis, alveolar hemorrhage, palpable purpura, and ANCA positivity) were generally similar among patients with and without remission. CONCLUSION: Mepolizumab is associated with clinical benefits for patients with and without a vasculitic EGPA phenotype.

4.
Front Immunol ; 13: 935996, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36091012

RESUMEN

In patients with hypereosinophilic syndrome (HES), mepolizumab reduces the incidence of HES-related clinical signs and symptoms (flares). However, reports characterizing flare manifestations are limited. The double-blind, parallel-group 200622 trial (NCT02836496) enrolled patients ≥12 years old with HES for ≥6 months, ≥2 flares in the previous year, and screening blood eosinophil count ≥1000 cells/µL. Patients maintained ≥4 weeks stable HES therapy, before randomization (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. This post hoc analysis investigated flare manifestations and duration by re-examining the Core Assessments form and narrative recorded for each flare during the study. Flare symptoms were retrospectively categorized into constitutional, dermatological, respiratory, nasal, gastrointestinal, neurologic and other. The most frequently reported flare symptoms were constitutional (94% of flares), dermatological (82% of flares) and respiratory (72% of flares); flares reported in patients receiving mepolizumab compared with placebo were generally similar in terms of the frequency of symptoms reported. Mepolizumab was associated with a shorter median (range) duration of flares (10.0 [4, 126] days) versus placebo (26.0 [1, 154] days). In patients with HES, flares were associated with symptoms linked to multiple organ systems highlighting the challenges faced for treating flares. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02836496, identifier NCT02836496.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndrome Hipereosinofílico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Niño , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/tratamiento farmacológico , Estudios Retrospectivos , Brote de los Síntomas
5.
Front Immunol ; 13: 840974, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35493455

RESUMEN

Background: Current standard-of-care treatments for hypereosinophilic syndrome (HES) include oral corticosteroids (OCS) and immunosuppressive/cytotoxic (IS/CT) therapies. The anti-IL-5 monoclonal antibody mepolizumab has also recently been approved for patients with this disease. The objective of this analysis was to assess the relationship between baseline therapy and flare reduction in patients with HES treated with mepolizumab, using data from the Phase III 200622 study (NCT02836496). Methods: In the double-blind, parallel-group 200622 study, eligible patients were ≥12 years old and had HES for ≥6 months, ≥2 flares in the previous 12 months, blood eosinophils ≥1000 cells/µL at screening and ≥4 weeks' stable HES therapy. Patients were randomised (1:1) to receive mepolizumab 300 mg subcutaneously or placebo every 4 weeks for 32 weeks plus their existing HES therapy. This post hoc, descriptive analysis assessed the effect of baseline HES therapy [IS/CT (± OCS), OCS No IS/CT, and No IS/CT/OCS] on the proportion of patients with ≥1 flare during the study period, the annualised rate of flares, time to first flare, and the proportion of patients with ≥1 flare during Weeks 20─32, with mepolizumab versus placebo. Results: Mepolizumab treatment was associated with a decrease in the proportion of patients who experienced ≥1 flare during the study period in all baseline therapy groups versus placebo (32-96% reduction). Similarly, the probability of a flare was lower with mepolizumab (14.3-31.4%) than placebo (35.7-74.1%) in all baseline therapy groups, as was the annualised flare rate (0.22-0.68 vs 1.14-1.62). The proportion of patients who experienced ≥1 flare during Weeks 20-32 was reduced with mepolizumab versus placebo for all baseline therapy groups (55-85% reduction). For all endpoints, the greatest effect of mepolizumab treatment was seen in the IS/CT (± OCS) group. Conclusions: Patients with poorly controlled HES are likely to achieve clinical benefit with mepolizumab in terms of flare reduction, regardless of their baseline therapy. Clinical Trial Registration: (https://clinicaltrials.gov/ct2/show/NCT02836496).


Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndrome Hipereosinofílico , Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Niño , Eosinófilos , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/tratamiento farmacológico , Inmunosupresores/uso terapéutico
6.
J Allergy Clin Immunol Pract ; 10(9): 2367-2374.e3, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35568330

RESUMEN

BACKGROUND: Mepolizumab, an anti-interleukin-5 (IL-5) antibody, reduces disease flares in patients with hypereosinophilic syndrome (HES). Factors predicting treatment response are unknown. OBJECTIVE: To assess mepolizumab efficacy by baseline blood eosinophil count (BEC) and serum IL-5 level in patients with HES. METHODS: This post hoc analysis used data from the phase III study assessing mepolizumab in patients with HES (NCT02836496). Patients 12 years old or older, with HES for 6 or more months, 2 or more flares in the previous year, and BEC ≥1,000 cells/µL at screening were randomized (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. The proportion of patients experiencing 1 or more flares (wk 32), annualized flare rate, and proportion of patients with change from baseline in Brief Fatigue Inventory (BFI) item 3 (wk 32), were analyzed by baseline BEC (<1500/≥1500 to <2500/≥2500 cells/µL). Flare outcomes were assessed by baseline serum IL-5 (<7.81/≥7.81 pg/mL). RESULTS: Across baseline BEC subgroups, mepolizumab reduced the proportion of patients experiencing 1 or more flares by 63% to 90% and flare rate by 58% to 84% (treatment-by-eosinophil interaction P = .76 and P = .90, respectively); patients had improved BFI item 3 score with mepolizumab versus placebo (cells/µL: <1,500: 54% vs 37%; ≥1,500 to <2,500: 47% vs 31%; ≥2,500: 61% vs 0%; treatment-by-eosinophil interaction P = .42). Most patients had undetectable baseline serum IL-5 levels; among these, mepolizumab versus placebo reduced the proportion of patients with 1 or more flares (77%) and flare rate (67%). CONCLUSIONS: Mepolizumab was efficacious in the patients with HES studied, irrespective of baseline BEC. Undetectable IL-5 levels should not preclude mepolizumab treatment.


Asunto(s)
Síndrome Hipereosinofílico , Interleucina-5 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Niño , Eosinófilos , Humanos , Síndrome Hipereosinofílico/tratamiento farmacológico
7.
J Allergy Clin Immunol Pract ; 10(8): 2125-2134, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35470096

RESUMEN

BACKGROUND: Hypereosinophilic syndrome (HES) is a group of rare hematologic disorders leading to eosinophil-driven tissue damage and dysfunction. Better understanding of HES variants may facilitate improved patient management. OBJECTIVE: To describe disease characteristics, treatment, and outcomes of patients with idiopathic (I-HES), myeloproliferative (M-HES), lymphocytic (L-HES), and chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) among HES case reports and aggregate data where available. METHODS: Relevant articles published between January 1, 2000, and March 20, 2020, were retrieved via PubMed; those reporting secondary, associated/reactive, overlap/single-organ, or familial HES were excluded. RESULTS: Of 188 articles included, 171 contained data on 347 separate HES cases (152 I-HES, 121 M-HES, 62 L-HES, 12 CEL-NOS). Based on individual data, mean age at diagnosis was 43 to 48 years for patients with all HES variants. Males accounted for 90% to 91% of M-HES/CEL-NOS and 55% to 65% of I-HES/L-HES cases. Cardiac symptoms were frequently observed for all HES variants (13%-22% of patients). Respiratory symptoms (I-HES), splenomegaly (M-HES and CEL-NOS), and skin conditions (L-HES) were also frequently observed. Bone marrow, heart, lung, spleen, liver, skin, and lymph nodes were commonly involved. Most patients with I-HES, L-HES, and CEL-NOS received corticosteroids (65%-85%), whereas most with M-HES received imatinib (81%); those with CEL-NOS also received interferon alpha (42%). CONCLUSIONS: Collective analysis of HES case reports supports and extends current understanding of HES variants, highlighting differences in signs and symptoms, organ involvement, and treatment approaches. Improved characterization of HES variants may facilitate the development of novel treatments.


Asunto(s)
Síndrome Hipereosinofílico , Corticoesteroides/uso terapéutico , Eosinófilos , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/tratamiento farmacológico , Mesilato de Imatinib , Leucemia , Masculino
8.
Allergy ; 77(3): 778-797, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34402066

RESUMEN

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.


Asunto(s)
Antiasmáticos , Asma , Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Eosinofilia Pulmonar , Corticoesteroides/uso terapéutico , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados , Síndrome de Churg-Strauss/tratamiento farmacológico , Eosinófilos , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Eosinofilia Pulmonar/tratamiento farmacológico , Resultado del Tratamiento
9.
J Allergy Clin Immunol Pract ; 9(12): 4431-4440.e1, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34389506

RESUMEN

BACKGROUND: A double-blind, placebo-controlled, phase III study (200622) showed that mepolizumab reduces disease flares for patients with uncontrolled FIP1-like-1-platelet-derived growth factor receptor α-negative hypereosinophilic syndrome (HES) and two or more flares in the previous year. OBJECTIVE: To further characterize the safety, clinical benefit, and pharmacodynamics of mepolizumab. METHODS: Eligible patients from both treatment arms of the double-blind study could enter an open-label extension study (205203; NCT03306043) to receive 4-weekly mepolizumab (300 mg subcutaneously) plus background therapy for 20 weeks. Primary end points were safety-based; other end points included flare rates and changes from baseline in mean daily oral corticosteroid (OCS) dose and blood eosinophil count. RESULTS: Of 104 patients who completed the double-blind study, 98% (previous placebo, n = 52; previous mepolizumab, n = 50) enrolled in the open-label extension. Overall, 66 of patients reported adverse events (AEs) (65%), 15 reported treatment-related AEs (15%), and nine reported serious AEs (9%). No events were fatal. The annualized flare rate (95% confidence interval) in the previous placebo and previous mepolizumab groups was 0.37 (0.16-0.86) and 0.14 (0.04-0.49) events/y, respectively. Of 72 patients receiving OCS during weeks 0 to 4, 20 (28%; previous placebo, n = 14; previous mepolizumab, n = 6) achieved 50% or greater reductions in mean daily dose during weeks 16 to 20. At week 20, blood eosinophil count was reduced by 89% in patients previously receiving placebo and remained reduced for those previously receiving mepolizumab. CONCLUSIONS: Extended mepolizumab treatment was associated with a positive benefit-risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α-negative HES.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndrome Hipereosinofílico , Corticoesteroides , Método Doble Ciego , Eosinófilos , Humanos , Síndrome Hipereosinofílico/tratamiento farmacológico , Resultado del Tratamiento
10.
Immun Inflamm Dis ; 9(4): 1447-1451, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34293251

RESUMEN

INTRODUCTION: Data on the burden of hypereosinophilic syndrome (HES) are limited. This study investigated the incidence and prevalence of HES using real-world data from patients in the United Kingdom. METHODS: Primary care data from the Clinical Practice Research Datalink were analyzed. The patients of interest were identified using medical codes specific for HES. Annual incidence rates and prevalence were estimated for the years 2010-2018 (inclusive) using patients observed for a minimum period of one year. RESULTS: Between 2010 and 2018, 93 patients were identified with HES. During the study period the incidence of HES ranged from less than 0.04, 95% confidence interval (CI) (0.01-0.07) to 0.17, 95% CI (0.10-0.26) per 100,000 person-years and the prevalence ranged from 0.15, 95% CI (0.10-0.25) to 0.89, 95% CI (0.74-1.09) cases per 100,000 persons. Sensitivity analyses varying the minimum observation period required to identify HES patients gave similar results. CONCLUSION: These results provide estimates of the burden of HES in the United Kingdom and indicate that whilst HES is a very rare disease, there is evidence that is increasingly being recorded in UK primary care.


Asunto(s)
Síndrome Hipereosinofílico , Bases de Datos Factuales , Humanos , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/epidemiología , Incidencia , Prevalencia , Reino Unido/epidemiología
12.
J Clin Rheumatol ; 27(3): 107-113, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-31693654

RESUMEN

OBJECTIVE: To estimate the prevalence and associated disease burden of eosinophilic granulomatosis with polyangiitis (EGPA) in patients with asthma from a US claims database. METHODS: Two cohorts were defined using enrollees (aged ≥18 years) from the Optum deidentified Clinformatics Datamart claims database 2010-2014, based on validated EGPA case definitions with varying specificity: EGPA 1 (main cohort; more specific; patients with 2 codes [in any combination] within 12 months of each other for eosinophilia, vasculitis, or mononeuritis multiplex) and EGPA 2 (sensitivity analysis cohort; less specific; patients with 2 codes of above conditions and/or neurologic symptoms within 12 months of each other). Patients had 3 or more asthma medications in the 12-month baseline before index date (date of the second code). Eosinophilic granulomatosis with polyangiitis prevalence, asthma severity during the baseline period, oral corticosteroid (OCS) use, and health care utilization during the 12-month follow-up period were determined. RESULTS: Overall, 88 and 604 patients were included in main cohort EGPA 1 and sensitivity analysis cohort EGPA 2, respectively; corresponding annual EGPA prevalence rates were 3.2 to 5.9 and 23.4 to 30.7 cases/million patients. Approximately 75% of patients were prescribed OCS and ~30% experienced 1 or more hospitalization; 75% in EGPA 1 and 52% in EGPA 2 with 1 or more non-OCS prescription in the 90 days before index date had severe asthma. CONCLUSIONS: Eosinophilic granulomatosis with polyangiitis prevalence estimates varied based on specificity of the case definition but were generally consistent with previous country-specific estimates. Despite differences in prevalence, both cohorts displayed a generally similar, high burden of OCS use and health care utilization, highlighting the substantial disease burden among patients with EGPA and the need for specific treatments.


Asunto(s)
Asma , Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Adolescente , Adulto , Asma/diagnóstico , Asma/tratamiento farmacológico , Asma/epidemiología , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamiento farmacológico , Síndrome de Churg-Strauss/epidemiología , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/epidemiología , Humanos , Aceptación de la Atención de Salud , Prevalencia
13.
J Allergy Clin Immunol ; 146(6): 1397-1405, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32956756

RESUMEN

BACKGROUND: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear. OBJECTIVE: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES. METHODS: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/µL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed. RESULTS: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]). CONCLUSIONS: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Síndrome Hipereosinofílico/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Niño , Método Doble Ciego , Eosinófilos/metabolismo , Humanos , Síndrome Hipereosinofílico/sangre , Recuento de Leucocitos , Persona de Mediana Edad
15.
Rheumatol Int ; 40(8): 1301-1307, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32009195

RESUMEN

Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p < 0.0008 (candidate variant) and p < 2.5 × 10-8 (genome-wide) analyses. Large genetic effects on mepolizumab-treatment response were not identified which could help differentiate responders from non-responders.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Síndrome de Churg-Strauss/tratamiento farmacológico , Glucocorticoides/administración & dosificación , Prednisolona/administración & dosificación , Adulto , Anciano , Síndrome de Churg-Strauss/genética , Eosinófilos/efectos de los fármacos , Femenino , Humanos , Interleucina-5 , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión
17.
J Allergy Clin Immunol ; 143(6): 2170-2177, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30578883

RESUMEN

BACKGROUND: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission. OBJECTIVE: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses. METHODS: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/µL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg. RESULTS: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/µL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395). CONCLUSION: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Granuloma Eosinófilo/tratamiento farmacológico , Eosinófilos/inmunología , Granulomatosis con Poliangitis/tratamiento farmacológico , Adulto , Método Doble Ciego , Femenino , Humanos , Interleucina-5/antagonistas & inhibidores , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Placebos , Prednisolona/uso terapéutico , Resultado del Tratamiento
18.
J Allergy Clin Immunol Pract ; 6(5): 1518-1527.e5, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29751154

RESUMEN

BACKGROUND: Conventional therapies for hypereosinophilic syndromes (HES) have variable efficacy and carry significant long-term toxicities. Anti-IL-5 (mepolizumab) therapy has a glucocorticoid (GC)-sparing effect in GC-sensitive HES, but the efficacy of mepolizumab in treatment-refractory HES patients with severe disease has not been examined to date. OBJECTIVE: To identify predictors of response to mepolizumab in subjects with severe treatment-refractory HES and compare long-term outcomes in these subjects with HES subjects treated with conventional therapies. METHODS: Retrospective analysis of clinical and laboratory data from 35 HES subjects treated with mepolizumab and 55 HES subjects on conventional therapy, all followed at a single center, was performed. RESULTS: Peak eosinophilia, GC sensitivity, pulmonary involvement, HES clinical subtype, and pretreatment serum IL-5 were correlated with mepolizumab response. Despite evidence of more severe disease at baseline, mepolizumab-treated subjects had comparable long-term clinical outcomes to HES subjects treated with conventional therapies and reported improvements in therapy-related comorbidities. Subjects managed with mepolizumab monotherapy had fewer disease flares than HES subjects on conventional therapies or mepolizumab-treated HES subjects requiring additional HES therapies. CONCLUSIONS: This study confirms that mepolizumab is an effective and well-tolerated therapy for HES, but suggests that response is more likely in GC-responsive subjects with idiopathic or overlap forms of HES. A primary benefit of treatment is the reduction of comorbidity due to discontinuation or the reduction of conventional HES therapies. Although subjects who completely discontinued GC had the most benefit, high-dose mepolizumab was a safe and effective salvage therapy for severe, treatment-refractory HES.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Eosinófilos/inmunología , Síndrome Hipereosinofílico/tratamiento farmacológico , Inmunoterapia/métodos , Adulto , Anciano , Progresión de la Enfermedad , Resistencia a Medicamentos , Femenino , Estudios de Seguimiento , Glucocorticoides/uso terapéutico , Humanos , Interleucina-5/antagonistas & inhibidores , Interleucina-5/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento
19.
N Engl J Med ; 376(20): 1921-1932, 2017 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-28514601

RESUMEN

BACKGROUND: Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti-interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis. METHODS: In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed. RESULTS: A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies. CONCLUSIONS: In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889 .).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome de Churg-Strauss/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Síndrome de Churg-Strauss/inmunología , Supervivencia sin Enfermedad , Método Doble Ciego , Quimioterapia Combinada , Eosinófilos , Femenino , Glucocorticoides/uso terapéutico , Humanos , Factores Inmunológicos/efectos adversos , Inyecciones Subcutáneas/efectos adversos , Análisis de Intención de Tratar , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión
20.
Ear Nose Throat J ; 89(3): E7-E11, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20229470

RESUMEN

Esophageal hamartoma is a rare entity, as only 7 cases have been previously reported in the English-language literature. Common symptoms include dysphagia, weight loss, and vomiting. Life-threatening airway obstruction can also occur. Because of the nonspecific nature of the symptoms, patients with these dangerous polyps are often misdiagnosed as having more common entities such as gastroesophageal reflux, peptic ulcer disease, or achalasia. Most of these tumors are missed on esophagoscopy and radiologic studies, and they can go undiagnosed for years. We diagnosed an esophageal hamartoma in an infant girl who had first presented when she was 8 days old with symptoms of apnea and cyanosis. The patient had undergone a multitude of tests since her birth, and she was eventually diagnosed with episodic bradycardia. When the patient was 6 weeks old, we discovered a polyp on nasopharyngolaryngoscopy, and we removed it by microdirect laryngoscopy and esophagoscopy. This patient was the youngest of the 8 who have now been reported to have been diagnosed with a hamartomatous polyp, and she was the only one to have presented with apnea (secondary to airway obstruction) and bradycardia. We recommend microdirect laryngoscopy and esophagoscopy to remove these pedunculated cervical esophageal lesions. A transcervical approach is warranted for sessile distal esophageal polyps. Esophageal polyps are an interesting entity in view of their rarity and intriguing presentations. Because esophageal obstructions can be life-threatening, further evaluation by laryngoscopy, bronchoscopy, and esophagoscopy is warranted when symptoms of dysphagia, vomiting, intermittent apnea, bradycardia, and weight loss persist despite conventional treatment.


Asunto(s)
Apnea/etiología , Bradicardia/etiología , Enfermedades del Esófago/complicaciones , Hamartoma/complicaciones , Antiulcerosos/uso terapéutico , Apnea/diagnóstico , Bradicardia/diagnóstico , Femenino , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Recién Nacido , Metoclopramida/uso terapéutico , Ranitidina/uso terapéutico
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