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1.
Medicina (B Aires) ; 81(2): 198-207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33906138

RESUMO

ANCA-associated vasculitis is a heterogeneous group of rare autoimmune conditions of unknown cause. Clinical characteristics and prognostic factors were analyzed in 47 patients: 20 (42.5%) with granulomatosis with polyangiitis, 17 (36.2%) with microscopic polyangiitis, 6 (12.8%) with renal-limited vasculitis, and 4 (8.5%) with eosinophilic granulomatosis with polyangiitis. Mean age at diagnosis was 53.5 ± 16.5 years and the median of BVAS (Birmingham Vasculitis Activity Score) was 14 (4-42). The most frequent clinical manifestations were: general in 44 (93.6%), renal in 30 (63.8%) and respiratory in 28 (59.6%). All received corticosteroids at the beginning of treatment. Intravenous cyclophosphamide was associated in 20 (42.5%) and oral route in 14 (29.8%); azathioprine in 3 (6.4%) and rituximab in 2 (4.2%). At a median follow-up of 35.5 months (range 0.14-234), 21 relapses were recorded in 14 patients. Overall mortality was 3.5 deaths per 100 patient-year in the whole group. Those over 55 years old, the presence of alveolar hemorrhage, those with FFS (Five Factor Score) of 2, and patients with MPA had poor prognosis. Renal involvement, ANCA pattern and BVAS were not associated to a poorer prognosis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Poliangiite Microscópica , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Síndrome de Churg-Strauss/epidemiologia , Humanos , Pessoa de Meia-Idade , Prognóstico
3.
N Engl J Med ; 384(7): 599-609, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33596356

RESUMO

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).


Assuntos
Compostos de Anilina/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Glucocorticoides/administração & dosagem , Ácidos Nipecóticos/uso terapêutico , Prednisona/administração & dosagem , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Administração Oral , Compostos de Anilina/efeitos adversos , Azatioprina/administração & dosagem , Ciclofosfamida/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucocorticoides/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Ácidos Nipecóticos/efeitos adversos , Prednisona/efeitos adversos , Recidiva , Indução de Remissão , Rituximab/administração & dosagem
4.
Front Immunol ; 11: 599417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362783

RESUMO

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.


Assuntos
Complemento C5a/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Nefropatias/tratamento farmacológico , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Nefropatias/imunologia , Nefropatias/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia
5.
BMJ Case Rep ; 13(12)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33370993

RESUMO

We report a novel case of a patient who presented with new diagnoses of both cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs) positive vasculitis and chronic lymphocytic leukaemia (CLL). The patient was a 79-year-old man who presented with melena, haemoptysis, acute hypoxia and acute kidney injury. In the current literature, there are rare associations of c-ANCA vasculitis and malignancy, but very few, if any, relating c-ANCA vasculitis and CLL. This case is unique due to the presence of both pathologies and an uncommon presentation of the vasculitis. He presented with renal and pulmonary findings, unlike the dermal manifestations commonly seen with vasculitis. We think that this could be an easily overlooked combination of diseases and, therefore, the purpose of this case is to prevent delays in care that could affect patient outcomes and also to encourage further research into the relationship between these diseases.


Assuntos
Lesão Renal Aguda/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Leucemia Linfocítica Crônica de Células B/diagnóstico , Pneumopatias/diagnóstico , Melena/imunologia , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/patologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Biópsia , Medula Óssea/patologia , Quimioterapia Combinada/métodos , Humanos , Rim/patologia , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/imunologia , Pulmão/diagnóstico por imagem , Pneumopatias/imunologia , Masculino , Melena/diagnóstico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
6.
Cochrane Database Syst Rev ; 9: CD008333, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32990324

RESUMO

BACKGROUND: Anti-neutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are a group of rare auto-inflammatory diseases that affects mainly small vessels. AAV includes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Anti-cytokine targeted therapy uses biological agents capable of specifically targeting and neutralising cytokine mediators of the inflammatory response. OBJECTIVES: To assess the benefits and harms of anti-cytokine targeted therapy for adults with AAV. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (2019, Issue 7), MEDLINE and Embase up to 16 August 2019. We also examined reference lists of articles, clinical trial registries, websites of regulatory agencies and contacted manufacturers. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials of targeted anti-cytokine therapy in adults (18 years or older) with AAV compared with placebo, standard therapy or another modality and anti-cytokine therapy of different type or dose. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included four RCTs with a total of 440 participants (mean age 48 to 56 years). We analysed the studies in three groups: 1) mepolizumab (300 mg; three separate injections every four weeks for 52 weeks) versus placebo in participants with relapsing or refractory EGPA; 2) belimumab (10 mg/kg on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised) or etanercept (25 mg twice a week) with standard therapy (median 25 months) versus placebo with standard therapy (median 19 months) in participants with GPA/MPA; and 3) infliximab (3 mg/kg on days 1 and 14, before the response assessment on day 42) versus rituximab (0.375g/m2 on days 1, 8, 15 and 22) in participants with refractory GPA for up to 12 months. None of the studies were assessed as low risk of bias in all domains: one study did not report randomisation or blinding methods clearly. Three studies were at high risk and one study was at unclear risk of bias for selective outcome reporting. One trial with 136 participants with relapsing or refractory EGPA compared mepolizumab with placebo during 52 weeks of follow-up and observed one death in the mepolizumab group (1/68, 1.5%) and none in the placebo group (0/68, 0%) (Peto odds ratio (OR) 7.39, 95% confidence interval (CI) 0.15 to 372.38; low-certainty evidence). Low-certainty evidence suggests that more participants in the mepolizumab group had ≥ 24 weeks of accrued remission over 52 weeks compared to placebo (27.9% versus 2.9%; risk ratio (RR) 9.5, 95% CI 2.30 to 39.21), and durable remission within the first 24 weeks sustained until week 52 (19.1% mepolizumab versus 1.5% placebo; RR 13.0, 95% CI 1.75 to 96.63; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% Cl 4 to 13). Mepolizumab probably decreases risk of relapse (55.8% versus 82.4%; RR 0.68, 95% CI 0.53 to 0.86; NNTB 4, 95% CI 3 to 9; moderate-certainty evidence). There was low-certainty evidence regarding similar frequency of adverse events (AEs): total AEs (96.9% versus 94.1%; RR 1.03, 95% CI 0.96 to 1.11), serious AEs (17.7% versus 26.5%; RR 0.67, 95% CI 0.35 to 1.28) and withdrawals due to AEs (2.9% versus 1.5%; RR 2.00, 95% CI 0.19 to 21.54). Disease flares were not measured. Based on two trials with different follow-up periods (mean of 27 months for etanercept study; up to four years for belimumab study) including people with GPA (n = 263) and a small group of participants with MPA (n = 22) analysed together, we found low-certainty evidence suggesting that adding an active drug (etanercept or belimumab) to standard therapy does not increase or reduce mortality (3.4% versus 1.4%; Peto OR 2.45, 95% CI 0.55 to 10.97). Etanercept may have little or no effect on remission (92.3% versus 89.5%; RR 0.97, 95% CI 0.89 to 1.07), durable remission (70% versus 75.3%; RR 0.93, 95% CI 0.77 to 1.11; low-certainty evidence) and disease flares (56% versus 57.1%; RR 0.98, 95% CI 0.76 to 1.27; moderate-certainty evidence). Low-certainty evidence suggests that belimumab does not increase or reduce major relapse (1.9% versus 0%; RR 2.94, 95% CI 0.12 to 70.67) or any AE (92.5% versus 82.7%; RR 1.12, 95% CI 0.97 to 1.29). Low-certainty evidence suggests a similar frequency of serious or severe AEs (47.6% versus 47.6%; RR 1.00, 95% CI 0.80 to 1.27), but more frequent withdrawals due to AEs in the active drug group (11.2%) compared to the placebo group (4.2%), RR 2.66, 95% CI 1.07 to 6.59). One trial involving 17 participants with refractory GPA compared infliximab versus rituximab added to steroids and cytotoxic agents for 12 months. One participant died in each group (Peto OR 0.88, 95% CI, 0.05 to 15.51; 11% versus 12.5%). We have very low-certainty evidence for remission (22% versus 50%, RR 0.44, 95% Cl 0.11 to 1.81) and durable remission (11% versus 50%, RR 0.22, 95% CI 0.03 to 1.60), any severe AE (22.3% versus 12.5%; RR 1.78, 95% CI 0.2 to 16.1) and withdrawals due to AEs (0% versus 0%; RR 2.70, 95% CI 0.13 to 58.24). Disease flare/relapse and the frequency of any AE were not reported. AUTHORS' CONCLUSIONS: We found four studies but concerns about risk of bias and small sample sizes preclude firm conclusions. We found moderate-certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably decreases disease relapse and low-certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of disease remission. There were similar frequencies of total and serious AEs in both groups, but the study was too small to reliably assess these outcomes. Mepolizumab may result in little to no difference in mortality. However, there were very few events. In participants with GPA (and a small subgroup of participants with MPA), etanercept or belimumab may increase the probability of withdrawal due to AEs and may have little to no impact on serious AEs. Etanercept may have little or no impact on durable remission and probably does not reduce disease flare.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Imunossupressores/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome de Churg-Strauss/tratamento farmacológico , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Imunossupressores/efeitos adversos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Poliangiite Microscópica/tratamento farmacológico , Pessoa de Meia-Idade , Números Necessários para Tratar , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Prevenção Secundária , Esteroides/administração & dosagem
7.
Tokai J Exp Clin Med ; 45(3): 126-130, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32901900

RESUMO

We present a case of osteomyelitis of the condyle secondary to bisphosphonate-related osteonecrosis of the jaw. A 77-year-old female was referred to our clinic with complaints of swelling in the left mandibular molar regions. The patient had been suffering from myeloperoxidase anti-neutrophil cytoplasmic antibody (MPOANCA) associated vasculitis and had been treated with glucocorticoids for 8 years, and oral bisphosphonates had been prescribed to prevent osteopenia secondary to glucocorticoids. Imaging examinations showed radiolucency of the left mandibular body. Based on the diagnosis of osteomyelitis of the mandibular body secondary to bisphosphonate-related osteonecrosis, the patient received antimicrobial therapy and was well-healed. However, the patient returned 8 weeks later complaining of acute left preauricular swelling. Computed tomography showed the destructive changes in the mandibular condyle. We speculated that the infection was caused by the local spread from osteomyelitis of the left mandibular body. The risk of jaw necrosis related to antiresorptive therapy is well known. In recent years, the number of older patients being administered glucocorticoids with bisphosphonates has increased; therefore, we must be attentive to the signs of infectious diseases of the jawbone in the aging because it can easily shift to osteomyelitis or osteonecrosis and spread infection through the marrow.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Arcada Osseodentária , Côndilo Mandibular , Osteomielite/etiologia , Idoso , Antibacterianos/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Feminino , Glucocorticoides/efeitos adversos , Humanos , Imagem por Ressonância Magnética , Côndilo Mandibular/diagnóstico por imagem , Osteomielite/diagnóstico por imagem , Osteomielite/terapia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
Ann Rheum Dis ; 79(9): 1243-1249, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32581088

RESUMO

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antirreumáticos/administração & dosagem , Glucocorticoides/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Quimioterapia Combinada , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do Tratamento , Adulto Jovem
10.
Clin Sci (Lond) ; 134(12): 1475-1489, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32538435

RESUMO

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1ß in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Cloridrato de Fingolimode/uso terapêutico , Peroxidase/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Anticorpos/imunologia , Apoptose , Feminino , Cloridrato de Fingolimode/farmacologia , Hematúria/complicações , Humanos , Células Jurkat , Rim/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proteinúria/complicações , Ratos Endogâmicos WKY , Transdução de Sinais
12.
Curr Allergy Asthma Rep ; 20(5): 13, 2020 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-32248398

RESUMO

PURPOSE OF REVIEW: Idiopathic pulmonary hemosiderosis (IPH) is one of the rarest and least understood causes of pulmonary hemorrhage in children. Illustrated by a complex case presentation, we discuss the clinical manifestations, diagnosis, pathology, proposed etiologies, and treatment of this rare disease. We also compare IPH with anti-glomerular basement membrane antibody syndrome (anti-GBM disease), another rare causes of pediatric pulmonary hemorrhage. RECENT FINDINGS: Recent retrospective studies regarding IPH along with advanced immunotherapy have led to an improved understanding of how to best treat this condition, potential associations, and improved prognosis. Pathogenesis remains unknown, but several reports have suggested involvement of the alveolar capillary basement membrane. IPH is a poorly understood disease of unknown etiology that is a diagnosis of exclusion. Our patient was diagnosed with IPH after an exhaustive workup, including lung biopsy, into other immune-mediated causes of disease. While the pathogenesis of this rare disease remains elusive, our patient's immunofluorescent staining along the alveolar basement membrane without evidence of circulating antibody to type IV collagen raises the question of an immune-mediated pathogenesis of the disease with involvement of the alveolar basement membrane.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Hemossiderose/diagnóstico , Pneumopatias/diagnóstico , Adolescente , Doença Antimembrana Basal Glomerular/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Biópsia , Diagnóstico Diferencial , Feminino , Glucocorticoides/uso terapêutico , Hemossiderose/tratamento farmacológico , Humanos , Pneumopatias/tratamento farmacológico , Metilprednisolona/uso terapêutico , Radiografia Torácica , Testes de Função Respiratória , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
14.
Farm. hosp ; 44(2): 46-50, mar.-abr. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-192387

RESUMO

OBJETIVO: Los pacientes incluidos en el ensayo MAINRITSAN2 recibieronuna pauta individualizada o un esquema fijo de rituximab como tratamiento de mantenimiento para la vasculitis asociada con anticuerpos contra el citoplasma de los neutrófilos. El objetivo de este estudio es comparar los costes reales de ambos esquemas de tratamiento. MÉTODO: Se llevó a cabo un análisis de minimización de costes sobre un periodo de 18 meses, estimando los costes directos -adquisición del fármaco, preparación, administración y costes de monitorización- desde la perspectiva del sistema de salud. Se realizaron varios análisis de sensibilidad con diferentes supuestos para los costes unitarios, añadiendo escenarios que incluían el rango intercuartílico de los resultados en el grupo de la pauta individualizada, diferente número de visitas de control para el grupo que seguía el esquema fijo y distinto número de eventos adversos registrados. Se realizó un análisis de coste-efectividad como parte del análisis de sensibilidad usan-do la diferencia absoluta en la tasa de recaída y su intervalo de confianza. RESULTADOS: El esquema de tratamiento con la pauta individualizada demostró una reducción del coste en comparación con el esquema de dosis fijas (6.049 versus 7.850 euros). El ahorro se debió principalmente a un menor coste en la adquisición del fármaco (2.861 versus 4.768 euros) y a menos costes de preparación y administración (892 versus 1.486 euros), debido al menor número de infusiones por paciente en el brazo del esquema individualizado. Este esquema individualizado presentó mayo-res costes de monitorización (2.296 versus 1.596 euros). Este resultado se repitió en todos los supuestos considerados en el análisis de sensibilidad desde el enfoque de minimización de costes. CONCLUSIONES: Desde la perspectiva del sistema de salud, la pauta individualizada parece ser la opción preferible en términos de costes directos. No obstante, son necesarios más estudios que evalúen todos los efectos y costes asociados al tratamiento de mantenimiento con rituximab de la vasculitis por anticuerpo anticitoplasma de neutrófilo para respaldar el manejo clínico y la asistencia sanitaria


OBJECTIVE: Patients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculi-tides. The aim of this study was to compare the real-world costs of both arms. METHOD: We performed a cost-minimization analysis over an 18-month time period, estimating direct costs-drug acquisition, preparation, administration and monitoring costs- from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost-effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. RESULTS: The individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from ower drug acquisition costs (2,861 vs. 4,768 euros) and lower prepara-tion and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailored-infusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. CONCLUSIONS: From the perspective of the health system, the tailored-therapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical ma-nagement and healthcare planning


Assuntos
Humanos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/economia , Rituximab/administração & dosagem , Rituximab/economia , Análise Custo-Eficiência , Custos de Medicamentos , Protocolos Clínicos
15.
BMJ ; 368: m421, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188597

RESUMO

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a small to medium vessel vasculitis associated with excess morbidity and mortality. This review explores how management of AAV has evolved over the past two decades with pivotal randomized controlled trials shaping the management of induction and maintenance of remission. Contemporary AAV care is characterized by approaches that minimize the cumulative exposure to cyclophosphamide and glucocorticoids, increasingly use rituximab for remission induction and maintenance, and consider therapies with less toxicity (for example, methotrexate, mycophenolate mofetil) for manifestations of AAV that do not threaten organ function or survival. Simultaneously, improvements in outcomes, such as renal and overall survival, have been observed. Additional trials and observational studies evaluating the comparative effectiveness of agents for AAV in various patient subgroups are needed. Prospective studies are necessary to assess the effect of psychosocial interventions on patient reported outcomes in AAV. Despite the expanding array of treatments for AAV, little guidance on how to personalize AAV care is available to physicians.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Imunossupressores/uso terapêutico , Azatioprina , Ciclofosfamida/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Indução de Remissão , Rituximab/uso terapêutico
16.
Autoimmun Rev ; 19(5): 102505, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173512

RESUMO

INTRODUCTION: The efficacy of rituximab (RTX) for remission induction and maintenance in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is now established, but the safety, particularly concerning severe infection risk, is not well known. OBJECTIVE: The purpose of this meta-analysis is to assess the prevalence and incidence of severe infections and the factors explaining heterogeneity in AAV patients treated with RTX. METHODS: PubMed and Embase were searched up to December 2017. Prevalence and incidence was pooled using a random-effects model in case of significant heterogeneity (I2 > 50%). Severe infection was defined as severe when it led to hospitalization, intravenous antibiotics therapy, and/or death. The heterogeneity was explored by subgroup analyses and meta-regression. RESULTS: The included studies encompassed 1434 patients with a median age of 51.9 years. The overall prevalence and incidence of severe infections was 15.4% (95% CI [8.9; 23.3], I2 = 90%, 33 studies) and 6.5 per 100 person-years (PY) (95% CI [2.9; 11.4], I2 = 76%, 18 studies), respectively. The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]). The prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1], I2 = 58%) including pneumocytis jirovecii infections (0.2%, 95% CI [0.0; 0.6], I2 = 0), irrespective of prophylaxis administration. Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I2 = 27%). The RTX cumulative dose was positively associated with prevalence of infections (13 studies, prevalence increase of 4% per 100 mg, p < .0001). The incidence of infection was negatively associated with duration of follow-up (8 studies, incidence decrease of 9% per year, p = .03). CONCLUSION: Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX. This meta-analysis highlights the need for prospective studies to stratify infectious risk and validate cumulative RTX dose and duration of follow-up as modifying factors.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Infecções/complicações , Rituximab/uso terapêutico , Humanos , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento
18.
Rheumatology (Oxford) ; 59(4): e24-e32, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32096545
19.
Medicine (Baltimore) ; 99(8): e19173, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080098

RESUMO

Recent large observational studies of antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) show that severe infection is a major cause of death and that the majority of infections occur during the early phase of initiating remission-induction therapy. Many risk factors for severe infection have been suggested, but these have been inconsistent. Nevertheless, infectious risk factors in elderly patients with AAV have not been adequately investigated in previous studies.In this retrospective observational study, we examined potential predictors of severe infection within 90 days (early severe infections) after remission-induction therapy in patients with AAV aged 65 years or older. We included 167 consecutive elderly patients with AAV admitted to our hospital. Data from medical history and remission-induction therapy were analyzed for predictive risk factors associated with early severe infections. The relationship between initial doses of corticosteroids and cumulative incidence of severe infections was also analyzed. A multivariate analysis of risk factors for early severe infections was performed using logistic regression analysis. The Kaplan-Meier method was used to estimate the overall survival, and the log-rank test was used to evaluate the differences between patients with and without early severe infections. Gray method was used to compare the cumulative incidence of severe infections in patients who did and did not receive initial high-dose corticosteroids.Logistic regression analysis showed that initial high-dose corticosteroid administration (prednisolone ≥0.8 mg/kg/d) (odds ratio [OR] 3.86, P = .030) and serum creatinine levels at diagnosis ≥1.5 mg/dL (OR 5.13, P = .003) were independent predictors of early severe infection although administration of cyclophosphamide or rituximab was not. The cumulative incidence of severe infections was also significantly higher in patients who received initial high-dose corticosteroids (P = .042), and patients with early severe infections exhibited a high mortality rate within 6 months (P < .001).Our findings suggest that initial high-dose corticosteroids and renal impairment at diagnosis are associated with a higher risk of early severe infections and early death in elderly patients with AAV.


Assuntos
Corticosteroides/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Infecções Bacterianas/epidemiologia , Insuficiência Renal/epidemiologia , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
20.
N Engl J Med ; 382(7): 622-631, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32053298

RESUMO

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Glucocorticoides/administração & dosagem , Falência Renal Crônica/prevenção & controle , Troca Plasmática , Administração Oral , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Terapia Combinada , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Incidência , Quimioterapia de Indução , Nefropatias/complicações , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Troca Plasmática/efeitos adversos , Rituximab/uso terapêutico
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