Successful use of eculizumab in immediate ANCA vasculitis recurrence in a pediatric kidney transplant.

BACKGROUND: Kidney transplantation is an acceptable therapy end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis with risk of disease recurrence ranging from 3% to 17%. Standard posttransplant immunosuppression is the mainstay of therapy after recurrence. Recently, new medications focused on complement regulation and avoidance of steroids have been shown to be effective in treating antineutrophil cytoplasmic antibody (ANCA) vasculitis with no studies in the pediatric population. METHODS: We report a 5-year-old patient with immediate recurrence of positive myeloperoxidase (MPO)-ANCA vasculitis after deceased donor kidney transplant and the novel use of eculizumab to salvage the graft. RESULTS: Eculizumab and transition to ravulizumab has been successful in improving graft function and maintenance of disease remission after immediate MPO-ANCA vasculitis recurrence posttransplant. CONCLUSIONS: Complement inhibitors may be used in addition to standard immunosuppression postkidney transplant in a pediatric patient with MPO-ANCA vasculitis recurrence without higher rates of infections.

Prospective study of complications and sequelae of glucocorticoid therapy in ANCA-associated vasculitis.

OBJECTIVE: Glucocorticoids (GC) are a cornerstone in treating antineutrophil cytoplasmic antibodies-associated vasculitides (AAV), however, they add to morbidity and mortality. To date, GC toxicity in AAV has rarely been systematically investigated. METHODS: Patients with a confirmed AAV were included in this monocentric prospective study. GC toxicity was assessed by structured interviews, clinical examination and electronic medical record analysis. The Glucocorticoid Toxicity Index (GTI) consisting of the Aggregate Improvement Score (GTI-AIS) and the Cumulative Worsening Score (GTI-CWS) was assessed at two time points (t1 baseline, t2 6 months later). We used regression analyses to assess the relationship between GTI and GC exposure, toxicity, and disease activity, and a receiver operating characteristic analysis to calculate a GC threshold dose beyond which toxicity is expected to occur. RESULTS: We included 138 patients with AAV. The median cumulative GC dose was 9014.0 mg. The most frequent adverse events were skin atrophy, osteoporosis and myopathy. GC exposure and toxicity were significantly correlated (p<0.001). GTI-AIS was significantly higher in active disease compared with patients in remission (p<0.001). GTI-CWS scored significantly higher in long-standing diseases (p=0.013) with high cumulative GC doses (p=0.003). Patients with a cumulative GC dose of 935 mg or more showed an 80% likelihood for a clinically meaningful change in GTI scoring. CONCLUSION: The GTI is capable of capturing GC toxicity in AAV and identifies patients at increased risk for GC side effects. Our data support efforts to limit GC exposure in patients with AAV.

Diagnosis and management of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated Vasculitis.

In 2021, the Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases was published. KDIGO is committed to providing the nephrology community with periodic updates, based on new developments for each disease. For patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), avacopan received regulatory approval in late 2021, leading to this KDIGO guideline update. In addition, the evidence supporting a lower-dose glucocorticoid induction regimen or even complete replacement of glucocorticoids has become stronger. Herein, an executive summary of the most important guideline changes from the AAV chapter is provided as a quick reference.

Characteristics and prognosis of acute renal failure on dialysis in ANCA vasculitis / Caractéristiques et pronostic des insuffisances rénales aiguës dialysées au cours des vascularites à ANCA

Renal involvement in ANCA (Anti Neutrophil Cytoplasmic Antigen) vasculitis is common and is associated with increased mortality with a significant risk of progression to end-stage renal disease. The aim of this study is to investigate the epidemiological, clinicopathological, therapeutic and evolutionary characteristics of patients with ANCA vasculitis with acute renal injury, and to evaluate the impact of haemodialysis in the acute phase on mortality and renal recovery. Secondary objectives are to investigate other risk factors that impact on overall and renal survival. 31 patients were included ; the mean follow-up time was 30 months. The mean age was 68.52 years, and the sex ratio 0.72. All patients had acute renal failure, with histology revealing a mixed form in 45% of cases and a sclerotic form in 12.9% of cases. Pulmonary involvement was found in 58% of cases. 71% of patients had ANCA with anti-myeloperoxydase specificity, and 25.8% anti-proteinase 3 specificity. 32.2% of patients required haemodialysis, of which 60% were weaned. As initial treatment, 58.1% of patients received cyclophosphamide and 35.5% rituximab. The relapse rate was 6.5%. Infectious and cardiovascular complications affected more than half of the patients. The mortality rate was 19.35%. Comparing the two groups of patients dialysed in the acute phase and not dialysed, it appears that the overall and renal mortality was comparable. The progression to end-stage renal failure was higher in the dialysis patients. In a multivariate study, the presence of chronic kidney disease in the history and pulmonary involvement were associated with higher mortality.

L'atteinte rénale au cours des vascularites à ANCA (anticorps anticytoplasmes des polynucléaires neutrophiles) est fréquente ; elle est associée à une surmortalité avec un risque important d'évolution vers l'insuffisance rénale terminale. L'objectif de ce travail est d'étudier les caractéristiques épidémiologiques, clinico-paracliniques, thérapeutiques et évolutives de patients atteints de vascularite à ANCA avec insuffisance rénale aiguë, et d'évaluer l'impact du recours à l'hémodialyse à la phase aiguë sur la mortalité et la récupération rénale. Les objectifs secondaires sont de rechercher d'autres facteurs de risque ayant un impact sur la survie globale et rénale. Trente et un patients ont été inclus, avec un délai moyen de suivi de 30 mois. L'âge moyen était de 68,5 ans, et le sex ratio de 0,72. Tous les patients avaient une insuffisance rénale aiguë, dont l'histologie a révélé une forme mixte dans 45 % des cas et une forme scléreuse dans 12,9 % des cas. Une atteinte pulmonaire était retrouvée dans 58 % des cas. Parmi les patients, 71 % (22) avaient des ANCA de spécificité anti-myélopéroxydase, contre 25,8 % (8) de spécificité anti-protéinase 3. Au total, 32,2 % des patients ont eu recours à l'hémodialyse, dont 60 % ont été sevrés. En traitement d'attaque, 58,1 % des patients ont reçu du cyclophosphamide et 35,5 % du rituximab. Le taux de rechutes était de 6,5 %. Les complications infectieuses et cardiovasculaires concernaient plus de la moitié des patients. Le taux de mortalité était de 19,35 %. En comparant les deux groupes des patients dialysés à la phase aiguë et non dialysés, il apparaît que la mortalité globale et rénale était comparable. L'évolution vers l'insuffisance rénale terminale était plus élevée chez les patients dialysés. En étude multivariée, la présence d'une insuffisance rénale chronique dans les antécédents et l'atteinte pulmonaire étaient associées à une surmortalité.

Urinary CD4 + T Cells Predict Renal Relapse in ANCA-Associated Vasculitis.

SIGNIFICANCE STATEMENT: Early identification of patients at risk of renal flares in ANCA vasculitis is crucial. However, current clinical parameters have limitations in predicting renal relapse accurately. This study investigated the use of urinary CD4 + T lymphocytes as a predictive biomarker for renal flares in ANCA vasculitis. This study, including urine samples from 102 patients, found that the presence of urinary CD4 + T cells was a robust predictor of renal relapse within a 6-month time frame, with a sensitivity of 60% and a specificity of 97.8%. The diagnostic accuracy of urinary CD4 + T cells exceeded that of ANCA titers, proteinuria, and hematuria. Monitoring urinary CD4 + T lymphocytes could help assess the risk of future renal relapse, enabling early preventive measures and tailored treatment strategies. BACKGROUND: In ANCA-associated vasculitis, there is a lack of biomarkers for predicting renal relapse. Urinary T cells have been shown to differentiate active GN from remission in ANCA-associated vasculitis, but their predictive value for renal flares remains unknown. METHODS: The PRE-FLARED study was a prospective multicenter biomarker study including 102 individuals with ANCA-associated vasculitis in remission aimed to predict renal relapse by quantifying urinary CD4 + T-cell subsets using flow cytometry at baseline and monitoring clinical outcomes over a 6-month follow-up. RESULTS: Among the participants, ten experienced renal relapses, two had non-renal flares, and 90 remained in stable remission. The median baseline urinary CD4 + T-cell count was significantly higher in patients who relapsed compared with those in remission. Receiver operating characteristic curve analysis of urinary CD4 + T-cell counts showed an area under the curve value of 0.88 for predicting renal flares, outperforming ANCA titers, hematuria, and proteinuria. Using a cutoff of 490 CD4 + T cells per 100 ml urine, the sensitivity and specificity in identifying patients with future renal flares were 60% and 97.8%, respectively. In a post hoc analysis, combining urinary CD4 + T-cell counts with proteinase-3 ANCA levels suggested improved predictive performance in the PR3 + subgroup. In addition, the number of urinary CD4 + T cells showed a limited correlation with a decline in GFR and an increase in proteinuria over the follow-up period. CONCLUSIONS: This study concluded that urinary CD4 + T-cell counts could identify patients with ANCA-associated vasculitis at a substantial risk of renal relapse within 6 months. Combining these counts with ANCA levels further improved the prediction of relapse. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Urinary T Lymphocytes Predict Renal Flares in Patients With Inactive ANCA-associated Glomerulonephritis (PRE-FLARED), NCT04428398 .

Granulomatous Polyangiitis Refractory to Induction With Rituximab in 3 Patients.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of immune-mediated diseases characterized by inflammation of small vessels, leading to endothelial injury with subsequent tissue damage. Current guidelines recommend induction therapy with rituximab over cyclophosphamide for severe disease activity. In this case series-based review, the authors discuss 3 cases of granulomatosis with polyangiitis (GPA) with proteinase-3 (PR3) disease that deteriorated following induction therapy with rituximab combined with mycophenolate mofetil and high-dose steroids. All 3 patients subsequently required salvage therapy with cyclophosphamide. Our experience suggests there is a temporal window where induction with rituximab is not fully effective, and deterioration or death can ensue. Expert recommendations do not offer a preferential protocol for induction with either rituximab or cyclophosphamide, with some even using a combination of both.

Trends in health care of patients with vasculitides, including giant cell arteritis, Takayasu arteritis, ANCA-associated vasculitis and Behçet's disease: cross-sectional data of the German National Database 2007-2021.

The aim of this study is to present the current care situation of patients with giant cell arteritis (GCA), Takayasu arteritis (TAK), ANCA-associated vasculitis (AAV) and Behçet's disease (BD). Trends over the last 15 years will reflect improvements and remaining deficits in the management of vasculitides. Consecutive cross-sectional data from patients with vasculitides from the German National Database (NDB) of the Collaborative Arthritis Centres between 2007 and 2021 were included. Medication, physician- and patient-reported outcomes on disease activity and disease burden, inpatient stays and occupational participation are compared for different vasculitis entities and over time. Employment rates were compared to German population rates. Between 502 and 854 vasculitis patients were annually documented. GCA and AAV were the most common vasculitides. Median disease duration ranged from 2 to 16 years. Over the years, glucocorticoids decreased in proportion and dose, most markedly in GCA and TAK, while biologic therapies increased up to 27%. Physicians rated disease activity as low for the vast majority of patients, while patients-reported moderate outcomes in many dimensions. PROs remained largely unchanged. The proportion of employed patients (< 65 years) increased from 47 to 57%. In recent years, biologics are increasingly used in patients with vasculitides, while glucocorticoids decreased significantly. PRO's have not improved. Work participation increased but remains lower than that in the German population.

Predictors of damage accrual in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A nationwide prospective study.

OBJECTIVES: This study elucidated the prognosis and risk factors associated with damage accrual during long-term remission maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We obtained data from 120 patients registered in a nationwide prospective cohort study on remission induction therapy in Japanese patients with AAV and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), who achieved remission at 24 months after treatment initiation and were followed up for additional 24 months. The primary outcome was the vasculitis damage index (VDI) score at Month 48, and the secondary outcome included risk factors associated with increased total VDI at Month 48. RESULTS: The understudied patients comprised 52 men and 68 women aged 68 ± 13 years. Between Months 25 and 48, the patients' survival rate was 95% (114/120). End-stage renal disease developed in seven patients by Month 48, and 64 cases had increased VDI. The multivariable analysis results revealed that oral prednisolone (PSL) doses at Month 24 were associated with damage accrual between Months 24 and 48. CONCLUSIONS: VDI accrual was observed in more than half of patients with AAV during maintenance therapy, and increased VDI scores were associated with oral PSL doses 24 months after initiating remission induction therapy in Japan.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

BACKGROUND: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. METHODS: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. RESULTS: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. CONCLUSIONS: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.

ANCA-associated scleritis: impact of ANCA on presentation, response to therapy and outcome.

OBJECTIVES: To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests. METHODS: This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests. RESULTS: A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]. CONCLUSION: Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.

Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying.

OBJECTIVES: This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. METHODS: Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. RESULTS: A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%-100% to 60%-100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%-91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. CONCLUSIONS: In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.

Efficacy and safety of avacopan in patients with ANCA-associated vasculitis receiving rituximab in a randomised trial.

OBJECTIVES: To evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial. METHODS: Key efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety. RESULTS: Of the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively. CONCLUSIONS: These data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab. TRIAL REGISTRATION NUMBER: NCT02994927.

Cardiovascular Disease in Anti-neutrophil Cytoplasm Antibody-Associated Vasculitis.

PURPOSE OF REVIEW: Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a rare, multisystem, autoimmune disease characterised by microvascular inflammation. Over the past 20 years, advances in immunological management have improved short-term patient outcomes. Longer-term patient outcomes remain poor with cardiovascular disease now the leading cause of death in AAV. Here, we examine the potential pathways that contribute to the increased risk of cardiovascular disease in AAV and the current evidence to manage this risk. RECENT FINDINGS: The incidence of cardiovascular disease in AAV exceeds that expected by traditional risk factors alone, suggesting a contribution from disease-specific factors. Similarly, it is unclear how different immunosuppressive therapies contribute to and modify cardiovascular risk, and there is a paucity of data examining the efficacy of traditional cardioprotective medications in AAV. There is a lack of evidence-based cardiovascular risk assessment tools and cardioprotective therapies in patients with AAV which should be addressed to improve long-term outcomes.

Clinical features and outcomes of small airway disease in ANCA-associated vasculitis.

BACKGROUND AND OBJECTIVE: To clarify the prevalence, features and outcomes of small airway disease (SAD) in a Chinese cohort with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) related pulmonary involvement. METHODS: SAD was recorded when the manifestations of either centrilobular nodules or air trapping were observed according to CT scans, except for infection or other airway-related comorbidities. Baseline and follow-up data were collected retrospectively. RESULTS: Of the 359 newly diagnosed AAV patients with pulmonary involvement, 92 (25.6%) had SAD, including 79 (85.9%) cases of anti-MPO-ANCA positive, 9 (9.8%) cases of anti-PR3-ANCA positive and 2 (2.2%) cases of double positive. Patients with SAD were more likely to be younger, female, non-smokers, have more ear-nose-throat (ENT) involvement, and have higher baseline Birmingham Vasculitis Activity Score (BVAS) compared to patients without SAD. Several AAV-related SAD patients have improved lung function and CT scans after immunosuppressive therapy. Patients with SAD had a better prognosis compared to those without SAD. When dividing all patients into three groups: isolated SAD (only small airway involvements), SAD with other lower airway involvements, and non-SAD, patients in the SAD with other lower airway involvements group had the highest risk of infection, while patients in the non-SAD group had the worst long-term outcomes. Similar results were observed in anti-MPO-ANCA positive patients when performing subgroup analyses. CONCLUSION: SAD is a unique manifestation of AAV-related lung involvement and exhibits distinct clinical features. It is vital to focus on SAD because of its association with prognosis and infection in AAV patients, especially in anti-MPO-ANCA positive patients. Moreover, SAD might represent a better response to immunosuppressors.

Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials.

OBJECTIVE: To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). METHODS: The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. RESULTS: 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). CONCLUSIONS: According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.