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1.
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
2.
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
3.
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
4.
Medicine (Baltimore) ; 99(5): e18857, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000387

RESUMO

RATIONALE: IgG4-related disease (IgG4-RD) is a slowly progressing inflammatory disease that can involve multiple organ systems. There is considerable overlap between IgG4-RDs and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Herein, we present an unusual case of IgG4-associated tubulointerstitial nephritis (IgG4-TIN) and ANCA-associated glomerulonephritis (ANCA-GN) co-occurring with C3 glomerulonephritis (C3GN). PATIENT CONCERNS: A 72-year-old male was admitted to hospital because of fever and fatigue. He was diagnosed with elevated serum creatinine and IgG4 levels, and was positive for ANCA. DIAGNOSIS: Initially, the pathology supported a diagnosis of IgG4-TIN and ANCA-GN; however, further examination revealed he also had C3GN. INTERVENTIONS: The patient was treated with methylprednisolone and cyclophosphamide and received regular follow-up care. OUTCOMES: After treatment, the patient no longer exhibited fever or fatigue and had no complications. The seven-month follow-up showed downward trends in IgG4 and MPO-ANCA levels and stable 24-hour urine protein, serum creatinine levels. LESSONS: Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and IgG4-associated tubulointerstitial nephritis with C3glomerulonephritis rarely occur simultaneously. Laboratory analysis and pathology are both needed to ensure diagnostic accuracy. However, in this case, the three diseases overlapped to such a large extent that achieving a definitive diagnosis was particularly challenging. Timely and accurate diagnosis is crucial for selecting the best treatment course and optimizing patient outcome.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Glomerulonefrite/diagnóstico , Nefrite Intersticial/diagnóstico , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Complemento C3/imunologia , Ciclofosfamida/uso terapêutico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G/imunologia , Imunossupressores/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Nefrite Intersticial/tratamento farmacológico , Nefrite Intersticial/imunologia
6.
Postgrad Med ; 131(8): 619-622, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31506001

RESUMO

Cytomegalovirus (CMV) infections are asymptomatic in immunocompetent patients but in immunocompromised patients, CMV infections have varying manifestations depending on their location. Patient who are organ transplant recipients, taking immunosuppressive therapy for a long time are at increased risk of CMV infections. CMV-induced gastric ulcer is very rare but many cases have been reported in the literature. No case describing association between CMV-related gastric ulcer and glomerulonephritis has been reported in the literature so far. In this article, we describe a case of pauci immune crescentic glomerulonephritis in a patient who was on rituximab and long-term steroid therapy and found to have CMV-related gastric ulcer. The association of small vessel vasculitis and CMV-related gastrointestinal infection has not been studied in the literature. Pauci immune crescentic glomerulonephritis is a subtype of rapidly progressive glomerulonephritis manifested by continuous loss of renal functions with features of dysmorphic red blood cells and glomerular proteinuria. Treatment of such condition is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen known as Rituximab. We also discussed the pathogenesis of CMV- induced gastric ulcer after rituximab therapy. This case emphasizes the importance of opportunistic infections in glomerulonephritis patients and raises the awareness that glomerunephritis patients are at increased risk of opportunistic infections as well. Rituximab was considered to be a safer drug but over the years, the incidence if opportunistic infections in patients on rituximab has been increasing.


Assuntos
Infecções por Citomegalovirus/complicações , Glomerulonefrite/tratamento farmacológico , Hospedeiro Imunocomprometido , Rituximab/uso terapêutico , Úlcera Gástrica/etiologia , Corticosteroides/uso terapêutico , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Glomerulonefrite/complicações , Humanos , Masculino , Rituximab/administração & dosagem , Rituximab/efeitos adversos
7.
Postgrad Med ; 131(7): 546-549, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31483199

RESUMO

Objectives: To identify the cognitive and functional deficits in a well-characterized group of patients with vasculitis of the nervous system. Methods: Sixty-seven patients diagnosed with Central Nervous System (CNS) or Peripheral nervous System (PNS) vasculitis over a 14-year period were retrospectively identified. Data on clinical presentation, laboratory, radiographic and tissue biopsy investigations, and treatment were collated. Cognitive, functional and quality of life evaluation assessments were performed in 31 patients who agreed to participate and included Addenbrooke's Cognitive Examination-revised (ACE-R), Nottingham Extended Activities of Daily Living (NEADL) and EQ-5D-3L quality of life questionnaires. Results: CNS vasculitis patients exhibited cognitive impairment, with a mean ACE-R score of 74/100 (standard deviation (SD) 16). NEADL and EQ-5D-3L scores were in the impaired range at 41/66 (SD 21) and 57/81 (SD 22), respectively. Patients with just PNS vasculitis exhibited fewer cognitive deficits with ACE-R and NEADL scores of 87 (SD 8) and 46 (SD 16) respectively. EQ-5D-3L score was in the impaired range of 65 (SD 22). Conclusions: Vasculitis of the nervous system and, in particular, CNS vasculitis causes cognitive impairment and deficits in functional ability. Such patients should be targeted for cognitive rehabilitation.


Assuntos
Disfunção Cognitiva/psicologia , Doenças do Sistema Nervoso Periférico/psicologia , Vasculite do Sistema Nervoso Central/psicologia , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/psicologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Estudos Transversais , Feminino , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/fisiopatologia , Arterite de Células Gigantes/psicologia , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/fisiopatologia , Granulomatose com Poliangiite/psicologia , Nível de Saúde , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Qualidade de Vida , Estudos Retrospectivos , Vasculite/complicações , Vasculite/tratamento farmacológico , Vasculite/fisiopatologia , Vasculite/psicologia , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/tratamento farmacológico , Vasculite do Sistema Nervoso Central/fisiopatologia , Adulto Jovem
8.
Internist (Berl) ; 60(10): 1106-1110, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31435719

RESUMO

We describe a patient with ANCA (antineutrophil cytoplasmic antibodies) associated vasculitis and acute-on-chronic renal failure. He had initially presented with severe pulmonary hemorrhage and anuric renal failure and improved rapidly with immunosuppressive therapy. Repeat renal biopsy revealed candida interstitial nephritis. Candida was also detected in bronchoalveolar lavage. Kidney function improved with long-term antifungal therapy. This report adds induction therapy for ANCA vasculitis to the conditions where invasive candidal infections including nephritis need to be considered.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antifúngicos/uso terapêutico , Candida/isolamento & purificação , Falência Renal Crônica/diagnóstico , Doença Aguda , Lesão Renal Aguda , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/microbiologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Biópsia , Candida/classificação , Candidíase/diagnóstico , Candidíase/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/microbiologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/tratamento farmacológico , Nefrite Intersticial/patologia , Resultado do Tratamento
9.
PLoS One ; 14(7): e0218705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291263

RESUMO

AIMS: Cytomegalovirus (CMV) infection under immunosuppression sometimes causes death. This study aimed to elucidate risk factors for CMV infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Patients with AAV who underwent remission induction treatment at Okayama University Hospital between 2006 and 2016 were retrospectively analyzed. The primary outcome was the development of CMV infection within 3 months. RESULTS: Of the 111 patients, 13 (11.7%) patients developed CMV infection. Patients with CMV infection were older (p = 0.030) and had a higher body mass index (p = 0.029) in comparison to those without CMV infection. A higher proportion had a severe form (p = 0.001) and granulomatosis with polyangiitis (GPA) (p = 0.001), as well as a higher Birmingham Vasculitis Activity Score (p = 0.018) and C-reactive protein (p = 0.018) levels at baseline. Using logistic regression analysis, severe form and GPA were independent risk factors (odds ratio [OR] = 9.68, 95% confidence interval [CI] = 1.92-60.23, and OR = 7.46, 95% CI = 1.46-47.60, respectively). In addition, patients with CMV infection were more likely than those without infection to be glucocorticoid-related diabetes mellitus (p = 0.025). CONCLUSION: Our study highlights disease severity and subgroups of AAV as risk factors for CMV infection.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Granulomatose com Poliangiite/imunologia , Infecções Oportunistas/imunologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Citomegalovirus/isolamento & purificação , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/virologia , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/patologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Japão , Modelos Logísticos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/etiologia , Infecções Oportunistas/virologia , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
10.
Mol Immunol ; 112: 394-398, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31291610

RESUMO

ANCA associated vasculitis is a serious, very often recurrent disease that despite the current standard treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk in the first year compared with healthy controls, attributed to infections, vasculitis activity, and renal disease. During the last few years, novel findings have suggested that activation of the complement system, in particular the alternative complement system, has a significant role in ANCA associated vasculitis pathogenesis. Detection of several components of this system in the circulation and urine reflects disease activity, and thus may be useful for clinical prognosis and to set up personalised treatments. In fact, some components of the complement system, such as C5a, might be potential targets for therapy. In this Review an update on clinical evidence for the role of complement activation in AAV is provided and subsequently we discuss potential therapeutic strategies that target complement components and open the way for clinical use of this target therapy in the near future.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Proteínas do Sistema Complemento/imunologia , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Ciclofosfamida/farmacologia , Glucocorticoides/farmacologia , Humanos , Rituximab/farmacologia
11.
Int J Med Sci ; 16(6): 838-844, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337957

RESUMO

The increased use of novel and powerful immunosuppressive drugs in kidney diseases may concomitantly expose the patients to higher risk of opportunistic infections, some of which still remain underdiagnosed thus mishandled. As such, we recently had a less prepared encounter of pulmonary nocardial infection in an ANCA-associated renal vasculitis patient under steroid therapy. Despite the use of broad-spectrum antimicrobials including micafungin, the infection was still unbridled and eventually culminated in lethal brain abscess. We thus chose to renew the knowledge of the clinical features, imaging manifestations, differential diagnosis, specific laboratory tests and unique treatment about this rare infection in kidney diseases patients under immunosuppressive therapy. In addition, CT images of easily confused pulmonary lesions superimposed on kidney diseases were also retrieved from our depository. Moreover, impaired renal function as a risk factor for infection and pharmacological options for the treatment were also focused. By sharing our hard-learnt experience and reviewing the literatures, our report may contribute to the awareness among the clinicians in general and nephrologists in particular of this rare disease in susceptible patients and facilitate a swift thus life-saving treatment.


Assuntos
Antibacterianos/uso terapêutico , Imunossupressores/efeitos adversos , Nocardiose/diagnóstico , Infecções Oportunistas/diagnóstico , Pneumonia Bacteriana/diagnóstico , Lesão Renal Aguda/complicações , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/terapia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Encéfalo/diagnóstico por imagem , Encéfalo/microbiologia , Abscesso Encefálico/diagnóstico , Abscesso Encefálico/tratamento farmacológico , Abscesso Encefálico/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Hospedeiro Imunocomprometido , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Nocardiose/tratamento farmacológico , Nocardiose/etiologia , Nocardia asteroides/isolamento & purificação , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/etiologia , Plasmaferese , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/etiologia , Tomografia Computadorizada por Raios X
12.
BMC Infect Dis ; 19(1): 664, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349802

RESUMO

BACKGROUND: Several studies have identified predictors of severe infections in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). However, the development of oral candidiasis (OC) as a predictor of subsequent severe infections has not been evaluated. The aim of this study was to assess the association between OC and subsequent severe infection requiring hospitalization during immunosuppressive therapy in AAV. METHODS: This single-center retrospective cohort study included 71 consecutive patients with newly diagnosed AAV from Aichi Medical University Hospital, Japan, starting immunosuppressive therapy between March 2013 and December 2018. The relationships between OC and subsequent severe infections were assessed using multivariate Cox proportional hazards models, adjusted for clinically relevant factors. RESULTS: During the follow-up period (median, 23 months; interquartile range, 11-51 months), 25 severe infectious episodes occurred in 19 patients (26.8%) and OC occurred in 17 patients (23.9%). A log-rank test showed that the OC group was significantly associated with severe infection (P <  0.001). Multivariate Cox proportional hazards models identified lower serum albumin (per 1 g/dl adjusted hazard ratio (HR)  = 0.38, 95% confidence interval (CI): 0.15-0.85; P  =  0.018), use of methylprednisolone pulse (adjusted HR  =  5.44, 95% CI: 1.54-20.0; P  =  0.010), and OC (adjusted HR  = 5.31, 95% CI: 1.86-15.8; P  =  0.002) as significant predictors of severe infection. Furthermore, a significant effect modification of the use of methylprednisolone pulse on OC was observed (P <  0.001). CONCLUSIONS: OC is one of the predictors of subsequent severe infections. The results suggest the importance of prolonging infection surveillance, especially for patients who developed OC under strong immunosuppressive therapy.


Assuntos
Candidíase Bucal/etiologia , Imunossupressores/efeitos adversos , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Feminino , Seguimentos , Humanos , Imunossupressão , Imunossupressores/administração & dosagem , Japão , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos
13.
Arthritis Rheumatol ; 71(11): 1888-1893, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31216123

RESUMO

OBJECTIVE: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. METHODS: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). RESULTS: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained. CONCLUSION: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Eritrócitos , Hemorragia/epidemiologia , Pneumopatias/epidemiologia , Embolia Pulmonar/epidemiologia , Urina/citologia , Trombose Venosa/epidemiologia , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Mieloblastina/imunologia , Peroxidase/imunologia , Modelos de Riscos Proporcionais , Fatores de Risco , Tromboembolia Venosa/epidemiologia
14.
Saudi J Kidney Dis Transpl ; 30(3): 726-734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249242

RESUMO

Rapidly progressive renal failure in anti-neutrophil cytoplasmic antibody (ANCA)- associated renal disease customarily implies crescentic glomerulonephritis with approximately 50% of the glomeruli will have crescents. The tubulointerstitial inflammation is often proportionate to the glomerular inflammation and may have granulomatous pattern adjacent to the glomeruli or an inflamed vessel. A 77-year-old male with rapidly progressive renal failure was myeloperoxidase-ANCA positive, and renal histopathology revealed thrombotic microangio-pathy, significant interstitial inflammation, interstitial granulomas, and arteritis. Pathology is unique for the paucity of the classical crescents and the myriad of extraglomerular features. His renal function improved and stabilized after induction with cyclophosphamide and maintenance with azathioprine.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/análise , Glomerulonefrite/patologia , Rim/patologia , Peroxidase/imunologia , Insuficiência Renal/patologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Humanos , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Rim/imunologia , Masculino , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/imunologia , Resultado do Tratamento
15.
J Immunol Res ; 2019: 1732175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198793

RESUMO

The purpose of this paper is to collect and summarize all evidences relating to an association between ANCA-associated vasculitides (AAVs) and hematologic malignancies, in the form of either a paraneoplastic vasculitis or leukemias and lymphomas developing on a preexisting vasculitis. Additionally, the role of cyclophosphamide in vasculitis treatment has been assessed and compared to rituximab. Paraneoplastic AAV seems to be an uncommon presentation of hemopathies. Hematologic malignancy risk in AAV is more likely to be increased by cyclophosphamide, although not yet definitely proven. Furthermore, the pathogenesis of ANCA-associated vasculitis has been reviewed with particular emphasis on the role of proteinase 3 (PR3) in fuelling granulomatosis with polyangiitis (GPA) inflammation. PR3 is a bactericidal protein expressed by neutrophilic granules and on their plasma membrane. Derangements in its expression and function have been linked to leukemias and GPA alike. PR3-derived PR1 peptide is being studied as an immunotherapy target in leukemia and multiple myeloma. This study is aimed at bringing together various evidences from the field of immunological and hematological research, at exposing contradictions, and at revealing novel insights on the association between ANCA-associated vasculitis and hematologic malignancies.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Ciclofosfamida/uso terapêutico , Granulomatose com Poliangiite/metabolismo , Neoplasias Hematológicas/metabolismo , Neutrófilos/imunologia , Rituximab/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Grânulos Citoplasmáticos/metabolismo , Granulomatose com Poliangiite/tratamento farmacológico , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Mieloblastina/metabolismo , Peptídeos/metabolismo
16.
Clin Exp Rheumatol ; 37 Suppl 117(2): 137-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31162031

RESUMO

OBJECTIVES: Rituximab was proven superior to azathioprine for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The high cost of rituximab might, however, limit its routine use. This study determined the cost-effectiveness of intravenous rituximab (5 x 500 mg until month 18), versus oral azathioprine (2 mg/kg per day, gradually decreased between month 12 and 22), for maintenance treatment of patients with granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited vasculitis, aged 18-75. METHODS: We performed a single-trial based economic evaluation. MAINRITSAN was a 28-month multicentre, prospective, randomised, controlled open-label trial. We estimated the cost of healthcare resources and quality of life using prospectively collected data. Healthcare costs were estimated from the perspective of the French Social Health Insurance's perspective, using 2016 tariffs for reimbursement. Utilities were derived from Short Form 36 scores. We estimated total average cost, incremental cost per incremental relapse averted and per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to assess uncertainty over relapses, severe adverse events, discount rate, utility weights, time horizon and the cost of rituximab. Costs drivers were tested using a generalised linear model. RESULTS: Total average costs were €13,387 (€11,605-€15,646) and €10,217 (€7,567-12,949) in the rituximab and azathioprine groups respectively. The incremental cost-effectiveness ratio (ICER) was €12,824 per relapse averted and the incremental cost-utility ratio (ICUR) €37,782 per QALY gained. Besides the unit cost of rituximab, the major cost drivers were relapses and severe adverse events. CONCLUSIONS: Maintenance treatment by rituximab could be cost-effective for preventing relapses in patients with AAV.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Azatioprina/economia , Rituximab/economia , Adolescente , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/economia , Anticorpos Anticitoplasma de Neutrófilos , Azatioprina/uso terapêutico , Análise Custo-Benefício , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Rituximab/uso terapêutico , Adulto Jovem
17.
Arthritis Rheumatol ; 71(11): 1879-1887, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31162829

RESUMO

OBJECTIVE: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. METHODS: Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels. RESULTS: Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. CONCLUSION: Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Metabolismo dos Lipídeos , Mieloblastina/imunologia , Peroxidase/imunologia , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Antirreumáticos/uso terapêutico , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/metabolismo , Azatioprina/uso terapêutico , Sedimentação Sanguínea , Doenças Cardiovasculares , Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/uso terapêutico , Índice de Gravidade de Doença
18.
Arthritis Rheumatol ; 71(11): 1812-1823, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31131994

RESUMO

OBJECTIVE: To evaluate predictors of serious infection events (SIEs) during rituximab (RTX) therapy and effects of hypogammaglobulinemia on SIE rates, and humoral response and its persistence after discontinuation of RTX in the treatment of rheumatic and musculoskeletal diseases (RMDs). METHODS: A retrospective longitudinal study of 700 RMD patients treated with RTX in a single center was conducted. Immunoglobulin levels were measured at baseline and at 4-6 months after each treatment cycle. Baseline predictors of SIEs were assessed using multivariable logistic regression; for RTX cycles 2-4, a mixed-effects logistic regression model was used. RESULTS: A total of 507 patients (72%) had rheumatoid arthritis, 94 (13%) had systemic lupus erythematosus, 49 (7%) had antineutrophil cytoplasmic antibody-associated vasculitis, and 50 (7%) had other RMDs. The number of SIEs recorded was 281 in 176 patients (9.8 per 100 person-years). Predictors of SIEs included non-RTX-specific comorbidities (previous history of SIE, cancer, chronic lung disease, diabetes mellitus, and heart failure), higher corticosteroid dose, and RTX-specific factors, including low IgG (<6 gm/liter) both at baseline and during treatment, RTX-associated neutropenia, higher IgM, and longer time to RTX re-treatment, but not B cell count or depletion status. Of 110 patients with low IgG, SIE rates were higher in those with low IgG at baseline (16.4 per 100 person-years) and in those who acquired low IgG during or after RTX treatment (21.3 per 100 person-years) versus those with normal IgG (9.7 per 100 person-years). Five of 8 patients (63%) had impaired humoral response to pneumococcus and hemophilus following vaccination challenge, and only 4 of 11 patients (36%) had IgG normalized after switching biologic disease-modifying antirheumatic drugs. CONCLUSION: Immunoglobulin levels should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Individualized risk-benefit assessment should be undertaken in those with lower IgG as this is a consistent SIE predictor and may increase infection profiles when RTX is switched to different therapies.


Assuntos
Agamaglobulinemia/induzido quimicamente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Rituximab/efeitos adversos , Adulto , Agamaglobulinemia/imunologia , Idoso , Comorbidade , Doenças do Tecido Conjuntivo/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Feminino , Glucocorticoides/administração & dosagem , Insuficiência Cardíaca/epidemiologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Estudos Longitudinais , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Neoplasias/epidemiologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Medição de Risco , Fatores de Risco , Escleroderma Sistêmico/tratamento farmacológico , Índice de Gravidade de Doença , Síndrome de Sjogren/tratamento farmacológico , Fatores de Tempo
19.
J Infect Chemother ; 25(7): 547-551, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30824299

RESUMO

Aspergillus fumigatus is the commonest cause of pulmonary aspergillosis; however, a recently developed molecular genetic technique identified A. lentulus as a sibling species. Most of the isolates were found in solid organ recipients, often associated with a fatal outcome. Moreover, there is concern that A. lentulus has low susceptibility to multiple antifungal agents. Herein, we report an adult immunocompromised patient with proven invasive pulmonary aspergillosis (IPA) caused by A. lentulus, which was identified through molecular genetic analysis. The patient was diagnosed with IPA by bronchoscopy 3 weeks after initiating systemic corticosteroid therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. The clinical course of IPA due to A. lentulus showed improvement after treatment with the antifungal agent voriconazole. In summary, we report an adult immunocompromised patient without a history of transplantation who was diagnosed with IPA due to A. lentulus successfully treated with voriconazole, and we also report the findings of a literature review on IPA caused by A. lentulus.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Aspergillus/patogenicidade , Glucocorticoides/efeitos adversos , Aspergilose Pulmonar Invasiva/microbiologia , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Antifúngicos/uso terapêutico , Aspergillus/isolamento & purificação , Broncoscopia , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/imunologia , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Tomografia Computadorizada por Raios X , Voriconazol/uso terapêutico
20.
J Clin Rheumatol ; 25(5): 217-223, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30896460

RESUMO

INTRODUCTION: The value of antineutrophil cytoplasmic antibody (ANCA) measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) to assess disease activity or predict relapse remains controversial, but recent evidence suggests a possible role for rituximab-treated patients. PATIENTS AND METHODS: All patients with active vasculitis and positive proteinase 3 (PR3)-ANCA who were starting a 2-year treatment course of rituximab for induction of remission at Addenbrooke's Hospital between January 2011 and January 2016 were included in this study. Common department practice consists of 6 g of rituximab given over 2 years, concomitant corticosteroids (0.5-1.0 mg/kg) with rapid taper over 3 months, and cessation of oral maintenance immunosuppressive agents at time of first rituximab dose. Clinical and laboratory data were collected retrospectively using electronic patient records. RESULTS: Fifty-seven patients with current PR3-ANCA positivity were included in the analysis. Median follow-up was 59 months. PR3-ANCA negativity was achieved in 25 patients (44%) with a median time of 14 months. Clinical remission was achieved in 53 patients (93%) with a median time of 3 months. Among the 53 patients who achieved remission during follow-up, 24 (45%) relapsed with a median time to relapse of 36 months from remission. Both PR3-ANCA-negative status and 50% reduction in PR3-ANCA from baseline (as time-varying covariates) were significantly associated with a longer time to relapse (PR3-ANCA-negative status: hazards ratio, 0.08 [95% confidence interval, 0.01-0.63, p = 0.016]; 50% reduction in PR3-ANCA: hazards ratio, 0.25 [95% confidence interval, 0.18-0.99, p = 0.046]). CONCLUSIONS: Achieving and maintaining PR3-ANCA negativity after rituximab was associated with longer-lasting remission.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Fatores Imunológicos/uso terapêutico , Mieloblastina/sangue , Rituximab/uso terapêutico , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão
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