RESUMO
Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important.
Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.
RESUMO
INTRODUCTION: Relapses in ANCA-associated vasculitis (AAV) increase the incidence of end-organ damage and their prevention requires prolonged immunosuppressive therapy. Rituximab, a type I anti-CD20 B cell depleting monoclonal antibody, is the current standard of care for induction of disease remission. Rituximab is not always effective and is associated with a high subsequent relapse risk. Obinutuzumab is a type II anti-CD20 humanised monoclonal antibody with the potential to obtain greater tissue B cell depletion than rituximab and reduce relapse risk in AAV. METHODS AND ANALYSIS: ObiVas is a randomised, phase II, double-blind controlled trial that will compare the mechanistic effects of rituximab and obinutuzumab in the induction treatment of patients with AAV positive for proteinase 3 ANCA (PR3-ANCA). 26 patients, either newly diagnosed or relapsing, will be recruited from a single centre and randomised in a 1:1 ratio to receive 1000 mg rituximab or obinutuzumab as induction therapy on days 1 and 15, alongside a tapering glucocorticoid regimen. The primary end point is CD19+ B cell depletion in nasal-associated lymphoid tissue (NALT), assessed as change from baseline to week 26. Secondary outcomes will compare the safety and clinical efficacy of rituximab and obinutuzumab and their impact on immune biomarkers, including tissue and peripheral blood lymphocyte subsets and PR3-ANCA binding levels. Patients are followed through to week 78. The trial opened for recruitment in January 2023 and is forecasted to complete recruitment by the end of 2024. ETHICS AND DISSEMINATION: For all patients, informed written consent will be obtained in keeping with Good Clinical Practice. Trial results will be disseminated to the relevant scientific, clinical and patient communities on trial closure. NALT data analysis will start before trial completion. Other analyses will be reported after trial completion. This trial was given ethical approval by Edgbaston (West Midlands) Research Ethics Committee (approval reference 22/WM/0174). TRIAL REGISTRATION NUMBER: ISRCTN13069630.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Monoclonais Humanizados , Rituximab , Humanos , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como Assunto , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/administração & dosagem , Masculino , FemininoRESUMO
SIGNIFICANCE STATEMENT: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 µ mol/L=0, K1: 250-450 µ mol/L=4, K2: >450 µ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821). CONCLUSIONS: The updated score optimizes clinicopathologic prognostication for clinical practice and trials.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Longitudinais , Estudos Retrospectivos , Rim , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Creatinina , Fatores de Risco , Fibrose , AtrofiaRESUMO
OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Azatioprina , Humanos , Azatioprina/uso terapêutico , Rituximab/uso terapêutico , Imunossupressores/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Recidiva , Indução de Remissão , Resultado do Tratamento , Ciclofosfamida/uso terapêutico , Anticorpos Anticitoplasma de NeutrófilosRESUMO
BACKGROUND: Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. METHODS: Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. PARTICIPANTS: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. INTERVENTIONS: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. OUTCOMES: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. DISCUSSION: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. TRIAL REGISTRATION: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Imunossupressores , Humanos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos/uso terapêutico , Imunossupressores/efeitos adversos , Proteômica , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab , Resultado do TratamentoRESUMO
In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting kidney damage or persistent disease, remains uncertain. To study this, our post hoc analysis included participants of five European randomized clinical trials on AAV (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, IMPROVE). Urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy (four-six months after treatment initiation) were correlated with the occurrence of a combined end point of death and/or kidney failure, or relapses during follow-up. Among 571 patients (59% men, median age 60), 60% had anti-proteinase 3-ANCA and 35% had anti-myeloperoxidase-ANCA, while 77% had kidney involvement. After induction therapy, 157/526 (29.8%) had persistent hematuria and 165/481 (34.3%) had UPCR of 0.05 g/mmol or more. After a median follow-up of 28 months (interquartile range 18-42), and adjustment for age, ANCA type, maintenance therapy, serum creatinine and persistent hematuria after induction, a UPCR of 0.05 g/mmol or more after induction was associated with significant risk of death/kidney failure (adjusted Hazard Ratio [HR] 3.06, 95% confidence interval 1.09-8.59) and kidney relapse (adjusted subdistribution HR 2.22, 1.16-4.24). Persistent hematuria was associated with significant kidney relapse (adjusted subdistribution HR 2.16, 1.13-4.11) but not with relapse affecting any organ nor with death/kidney failure. Thus, in this large cohort of patients with AAV, persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse. Hence, these parameters must be considered to assess long-term kidney prognosis of patients with AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Insuficiência Renal , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Hematúria/etiologia , Hematúria/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Proteinúria/etiologia , Indução de Remissão , Doença Crônica , Insuficiência Renal/complicações , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: Dialysis patients and immunosuppressed renal patients are at increased risk of COVID-19 and were excluded from vaccine trials. We conducted a prospective multicentre study to assess SARS-CoV-2 vaccine antibody responses in dialysis patients and renal transplant recipients, and patients receiving immunosuppression for autoimmune disease. METHODS: Patients were recruited from three UK centres (ethics:20/EM/0180) and compared to healthy controls (ethics:17/EE/0025). SARS-CoV-2 IgG antibodies to spike protein were measured using a multiplex Luminex assay, after first and second doses of Pfizer BioNTech BNT162b2(Pfizer) or Oxford-AstraZeneca ChAdOx1nCoV-19(AZ) vaccine. RESULTS: Six hundred ninety-two patients were included (260 dialysis, 209 transplant, 223 autoimmune disease (prior rituximab 128(57%)) and 144 healthy controls. 299(43%) patients received Pfizer vaccine and 379(55%) received AZ. Following two vaccine doses, positive responses occurred in 96% dialysis, 52% transplant, 70% autoimmune patients and 100% of healthy controls. In dialysis patients, higher antibody responses were observed with the Pfizer vaccination. Predictors of poor antibody response were triple immunosuppression (adjusted odds ratio [aOR]0.016;95%CI0.002-0.13;p < 0.001) and mycophenolate mofetil (MMF) (aOR0.2;95%CI 0.1-0.42;p < 0.001) in transplant patients; rituximab within 12 months in autoimmune patients (aOR0.29;95%CI 0.008-0.096;p < 0.001) and patients receiving immunosuppression with eGFR 15-29 ml/min (aOR0.031;95%CI 0.11-0.84;p = 0.021). Lower antibody responses were associated with a higher chance of a breakthrough infection. CONCLUSIONS: Amongst dialysis, kidney transplant and autoimmune populations SARS-CoV-2 vaccine antibody responses are reduced compared to healthy controls. A reduced response to vaccination was associated with rituximab, MMF, triple immunosuppression CKD stage 4. Vaccine responses increased after the second dose, suggesting low-responder groups should be prioritised for repeated vaccination. Greater antibody responses were observed with the mRNA Pfizer vaccine compared to adenovirus AZ vaccine in dialysis patients suggesting that Pfizer SARS-CoV-2 vaccine should be the preferred vaccine choice in this sub-group.
Assuntos
Doenças Autoimunes , COVID-19 , Vacinas Virais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Ácido Micofenólico , Diálise Renal , Rituximab , SARS-CoV-2RESUMO
BACKGROUND: The disease course of adult immunoglobulin A (IgA) vasculitis (IgAV; Henoch-Schönlein purpura) has not been well defined. METHODS: In a retrospective survey, we studied 85 adult IgAV patients with extended follow-up (median 43 months) for 67 patients. RESULTS: Only 33 of 67 (49%) achieved complete remission. Ongoing renal disease was the most common persistent organ manifestation, but extra-renal disease activity was also present in >50% of patients not achieving complete remission. Twenty-nine of 67 (43%) had relapsing disease, with 18/67 (27%) experiencing several relapses. Skin disease was the most common feature in relapsing patients, followed by nephritis. At 4 years of follow-up, 6 of 29 (21%) experienced progressive disease and 10/29 (34%) relapsing disease. Five of 67 (7%) developed nephritis after diagnosis, within the first 6 months of follow-up. At final follow-up, 10 of 67 (15%) had chronic kidney disease Stage ≥G3a, 18 (27%) haematuria and 13 (19%) proteinuria. No therapy appeared particularly effective and only 6/17 patients treated with mycophenolate mofetil experienced a good response. CONCLUSIONS: The disease course of adult IgAV is different from that seen in children, with higher frequency of persisting and relapsing disease. Renal disease is the main determinant of ongoing disease activity, but extra-renal features were seen in >50% of patients with chronic disease activity. No clear conclusions on use or choice of immunosuppressive agent could be made based on our experience.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Prednisolona/administração & dosagem , Rituximab/administração & dosagem , Injúria Renal Aguda/imunologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Humanos , Masculino , RecidivaAssuntos
Transplante de Pulmão , Complicações Pós-Operatórias , Vasculite , Adulto , Fibrose Cística/cirurgia , Humanos , MasculinoAssuntos
Eosinofilia/tratamento farmacológico , Doenças Orbitárias/tratamento farmacológico , Adulto , Eosinofilia/complicações , Eosinofilia/patologia , Feminino , Fibrose , Glucocorticoides/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Órbita/patologia , Doenças Orbitárias/etiologia , Doenças Orbitárias/patologia , Prednisolona/administração & dosagem , Gravidez , Rituximab/administração & dosagemAssuntos
COVID-19 , Glomerulonefrite , Nefrite , Membrana Basal , Membrana Basal Glomerular , Humanos , Inflamação , Pandemias , SARS-CoV-2RESUMO
OBJECTIVES: Following a maintenance course of rituximab (RTX) for ANCA-associated vasculitis (AAV), relapses occur on cessation of therapy, and further dosing is considered. This study aimed to develop relapse and infection risk prediction models to help guide decision making regarding extended RTX maintenance therapy. METHODS: Patients with a diagnosis of AAV who received 4-8 grams of RTX as maintenance treatment between 2002 and 2018 were included. Both induction and maintenance doses were included; most patients received standard departmental protocol consisting of 2× 1000 mg 2 weeks apart, followed by 1000 mg every 6 months for 2 years. Patients who continued on repeat RTX dosing long-term were excluded. Separate risk prediction models were derived for the outcomes of relapse and infection. RESULTS: A total of 147 patients were included in this study with a median follow-up of 63 months [interquartile range (IQR): 34-93]. Relapse: At time of last RTX, the model comprised seven predictors, with a corresponding C-index of 0.54. Discrimination between individuals using this model was not possible; however, discrimination could be achieved by grouping patients into low- and high-risk groups. When the model was applied 12 months post last RTX, the ability to discriminate relapse risk between individuals improved (C-index 0.65), and once again, clear discrimination was observed between patients from low- and high-risk groups. Infection: At time of last RTX, five predictors were retained in the model. The C-index was 0.64 allowing discrimination between low and high risk of infection groups. At 12 months post RTX, the C-index for the model was 0.63. Again, clear separation of patients from two risk groups was observed. CONCLUSION: While our models had insufficient power to discriminate risk between individual patients they were able to assign patients into risk groups for both relapse and infection. The ability to identify risk groups may help in decisions regarding the potential benefit of ongoing RTX treatment. However, we caution the use of these prediction models until prospective multi-centre validation studies have been performed.