Long-term outcome of kidney function in patients with ANCA-associated vasculitis.

BACKGROUND: Kidney involvement is common in ANCA associated vasculitis (AAV) and prognosis determined by the severity of kidney damage. This study focused on long-term kidney outcomes, defining possible risk factors and comparing the performance of three different histological classifications to predict outcomes for patients with AAV. METHODS: The dataset included 848 patients with newly diagnosed AAV who participated in 7 RCTs (1995-2012). Follow up information obtained from questionnaires sent to the principal investigators of the original RCTs. RESULTS: The cumulative incidence of end-stage kidney disease (ESKD) at 5 and 10 years was 17% and 22%, respectively. Patients who developed ESKD had reduced patient survival compared to those with preserved kidney function (HR: 2.8, P-value < 0.001). Comparing patients with AAV and kidney involvement to a matched general population, patients with AAV had poor survival outcomes, even in early stages of CKD. The main cause of death was infection followed by cardiovascular disease in patients developing ESKD and malignancy in those who did not. 34% of patients with initial need for dialysis recovered kidney function after treatment. 35 out of 175 in need of kidney replacement therapy (KRT) during follow up received a kidney transplant with good outcome; 86% patient survival at 10 years.In the subcohort of 214 patients with available kidney biopsies, three scoring systems were tested: the Berden classification, the Renal Risk Score (RRS), and the Mayo Clinic Score (MCCS). The scores highlighted the importance of normal glomeruli and severe glomerulosclerosis on kidney survival (P < 0.001 and P = 0.001, respectively). The RRS demonstrated a moderate prediction of kidney survival (AUC: 0.79; SE: 0.03, 95% CI: 0.71-0.83). CONCLUSIONS: Early diagnosis is extremely important. Even milder forms of kidney involvement have an impact on the prognosis. Patients in need of KRT had the lowest survival rates, but kidney transplantation has shown favorable outcomes for eligible AAV patients. The three histologic scoring systems were all identified as independent prognostic factors for kidney outcome.

Long-term outcomes and prognostic factors for survival of patients with ANCA-associated vasculitis.

BACKGROUND: Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors. METHODS: Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models. RESULTS: A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9-13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model. CONCLUSIONS: Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV.

Perspective on COVID-19 vaccination in patients with immune-mediated kidney diseases: consensus statements from the ERA-IWG and EUVAS.

Patients with immune-mediated kidney diseases are at increased risk of severe coronavirus disease 2019 (COVID-19). The international rollout of COVID-19 vaccines has provided varying degrees of protection and enabled the understanding of vaccine efficacy and safety. The immune response to COVID-19 vaccines is lower in most patients with immune-mediated kidney diseases; either related to immunosuppression or comorbidities and complications caused by the underlying disease. Humoral vaccine response, measured by the presence of antibodies, is impaired or absent in patients receiving rituximab, mycophenolate mofetil (MMF), higher doses of glucocorticoids and likely other immunosuppressants, such as cyclophosphamide. The timing between the use of these agents and administration of vaccines is associated with the level of immune response: with rituximab, vaccine response can only be expected once B cells start to recover and patients with transient discontinuation of MMF mount a humoral response more frequently. The emergence of new COVID-19 variants and waning of vaccine-induced immunity highlight the value of a booster dose and the need to develop mutant-proof vaccines. COVID-19 vaccines are safe, exhibiting a very low risk of de novo or relapsing immune-mediated kidney disease. Population-based studies will determine whether this is causal or coincidental. Such cases respond to standard management, including the use of immunosuppression. The Immunonephrology Working Group and European Vasculitis Society recommend that patients with immune-mediated kidney diseases follow national guidance on vaccination. Booster doses based on antibody measurements could be considered.

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

OBJECTIVE: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. METHODS: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. CONCLUSION: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

Renal relapse in antineutrophil cytoplasmic autoantibody-associated vasculitis: unpredictable, but predictive of renal outcome.

Objectives: To determine predictors of renal relapse and end-stage renal failure (ESRF) in patients with ANCA-associated vasculitis. Methods: Data from four European Vasculitis Society randomized controlled trials, conducted roughly simultaneously between 15 March 1995 and 30 September 2002, was pooled to determine predictors of long-term renal outcome. The respective trial inclusion criteria covered the entire spectrum of disease severity. Baseline predictors of time to first renal relapse and time to ESRF were assessed by competing events analysis and Cox proportional hazards regression. The effect of renal relapse on time to ESRF was assessed by adding renal relapses to the competing events analysis as a time-varying covariate. Results: The number of patients participating was 535; mean serum creatinine (±s.d.) at entry was 341 ± 321 µmol/l and 19.7% developed ESRF. One or more renal relapse(s) was experienced by 101 patients. Multivariable regression analysis demonstrated that, in addition to impaired baseline renal function, developing ⩾1 renal relapse was an independent risk factor for ESRF (subhazard ratio 9; 95% CI 4, 19; P < 0.001). No predictive factors for renal relapse were found. Conclusion: In addition to baseline renal function, the occurrence of renal relapses is an important determinant of ESRF in patients with ANCA-associated vasculitis. We did not find any clinical predictors for renal relapse itself, including disease activity elsewhere. In light of the silent nature of renal relapse in ANCA-associated vasculitis, we stress the need for long-term vigilant monitoring for early signs of renal relapse and propose performing 3-monthly urinalysis. This will enable timely treatment and help further improve renal outcome.

Clinical associations with venous thromboembolism in anti-neutrophil cytoplasm antibody-associated vasculitides.

Objective: To assess potential associations for the development of venous thromboembolic events in patients with ANCA-associated vasculitides (AAV). Methods: Four hundred and seventeen patients enrolled to participate in randomized controlled trials conducted by the European Vasculitis Society were identified. Univariate and multivariate analyses were performed to validate previously proposed and identify novel risks associated with venous thromboembolism (VTE) in AAV. Results: VTE occurred in 41 of 417 (9.8%) patients. Uncorrected univariate analysis identified BVAS (odds ratio, OR = 1.05, 95% CI: 1.01, 1.10; P = 0.013), subsequent development of malignancy (OR = 2.6, 95% CI: 1.19, 5.71; P = 0.017), mucous membrane or eye involvement (OR = 2.13, 95% CI: 1.10, 4.11; P = 0.024) and baseline creatinine (OR = 1.08, 95% CI: 0.99, 1.18; P = 0.037) as being associated with the development of VTE. Multivariate analysis highlighted CRP (per 10 mg/l increase, OR = 1.05, 95% CI: 1.01, 1.09; P = 0.025), cutaneous involvement (OR = 4.83, 95% CI: 1.63, 14.38; P = 0.005) and gastrointestinal involvement (OR = 6.27, 95% CI: 1.34, 29.37; P = 0.02) among the BVAS items as well as baseline creatinine (per 100 µmol/l increase, OR = 1.17, 95% CI: 1.02, 1.35; P = 0.029) as being associated with VTEs. Conclusion: Our results highlight a role of CRP, baseline creatinine, and cutaneous and gastrointestinal involvement in the risk stratification as being associated with thromboembolic events. Moreover, there might be an association between VTEs and subsequent development of malignancy and disease activity in general.

Long term azathioprine maintenance therapy in ANCA-associated vasculitis: combined results of long-term follow-up data.

Objective: We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up. Methods: Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months. Results: During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative). Conclusion: Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually.

Damage in the anca-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials.

OBJECTIVES: To describe short-term (up to 12 months) and long-term (up to 7 years) damage in patients with newly diagnosed antineutrophil-cytoplasm antibody-associated vasculitis (AAV). METHODS: Data were combined from six European Vasculitis Study group trials (n=735). Long-term follow-up (LTFU) data available for patients from four trials (n=535). Damage accrued was quantified by the Vasculitis Damage Index (VDI). Sixteen damage items were defined a priori as being potentially treatment-related. RESULTS: VDI data were available for 629 of 735 patients (85.6%) at baseline, at which time 217/629 (34.5%) had ≥1 item of damage and 32 (5.1%) ≥5 items, reflecting disease manifestations prior to diagnosis and trial enrolment. LTFU data were available for 467/535 (87.3%) at a mean of 7.3 years postdiagnosis. 302/535 patients (56.4%) had VDI data at LTFU, with 104/302 (34.4%) having ≥5 items and only 24 (7.9%) no items of damage. At 6 months and LTFU, the most frequent items were proteinuria, impaired glomerular filtration rate, hypertension, nasal crusting, hearing loss and peripheral neuropathy. The frequency of damage, including potentially treatment-related damage, rose over time (p<0.01). At LTFU, the most commonly reported items of treatment-related damage were hypertension (41.5%; 95% CI 35.6 to 47.4%), osteoporosis (14.1%; 9.9 to 18.2%), malignancy (12.6%; 8.6 to 16.6%), and diabetes (10.4%; 6.7 to 14.0%). CONCLUSIONS: In AAV, renal, otolaryngological and treatment-related (cardiovascular, disease, diabetes, osteoporosis and malignancy) damage increases over time, with around one-third of patients having ≥5 items of damage at a mean of 7 years postdiagnosis.

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial.

OBJECTIVES: The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS: Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS: The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS: At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER: ISRCTN28528813.

Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials.

OBJECTIVE: Granulomatosis with polyangiitis and microscopic polyangiitis are ANCA-associated vasculitides (AAVs). The Vasculitis Damage Index (VDI) quantifies damage. This study aims to determine the factors associated with long-term damage in the AAVs. METHODS: Data from 535 patients from four European Vasculitis Study Group trials were studied. A long-term follow-up (LTFU) questionnaire at 7 years post-diagnosis was completed. The associations between baseline (age, creatinine and BVAS score) and cumulative (number of relapses and duration of glucocorticoid use) factors and damage accrued (total VDI scores and individual treatment-related damage items) during follow-up were explored. Multiple regressions identified independent associations between baseline measures, cumulative factors and VDI scores at LTFU. RESULTS: Two hundred and ninety-six patients had glucocorticoid use and VDI data available at LTFU, with the mean length of glucocorticoid use being 40.4 months (S.D. 16.7). High levels of damage were independently associated with older age at baseline (P = 0.051), lower glomerular filtration rate (P = 0.041), higher BVAS scores (P = 0.046), increased cumulative glucocorticoid use (P = 0.016) and increasing number of relapses. Patients with longer duration of glucocorticoid treatment were more likely to have a total VDI score ≥5 [odds ratio 1.26 per 12 months of glucocorticoid use (95% CI 1.03, 1.53), P = 0.022]. The main limitation is that approximately half of the patients enrolled had no LTFU data available; these patients were older with more severe initial disease. CONCLUSION: Long-term damage in the AAVs may be associated with severity of initial disease, age, number of relapses and duration of glucocorticoid use.

The long-term outcomes of systemic vasculitis.

Patients with generalized ANCA-associated small vessel vasculitis (AAV) have a very poor outcome if the ANCA-associated vasculitis is not diagnosed, evaluated and treated properly. The introduction of treatment with immunosuppressive therapy has improved patient survival dramatically but with considerable side effects. Besides, almost 50% of surviving patients experience a relapse of vasculitis. Since 1995, the European Vasculitis Society (EUVAS) has designed and conducted several clinical trials on patients with AAV independently of pharmaceutical companies. The studies included patients with newly diagnosed AAV and were stratified according to renal function and generalized versus more localized forms. As the immediate patient survival has improved, the longer term outcome has become more important. There are several reports on outcome of patients with ANCA-associated vasculitis, but the patient groups were heterogeneous regarding diagnosis as well as treatment and follow-up. Therefore, EUVAS decided to further evaluate the effect and possible adverse events of the original randomized trials. This review presents an overview on long-term follow-up of patients with ANCA-associated vasculitis, with focus on relapse rate, patient and renal survival and development of cardiovascular disease and malignancy.

A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.

Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear.

Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 µmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.

BACKGROUND: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. METHODS: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. RESULTS: The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). CONCLUSIONS: A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis.

BACKGROUND: Granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) are subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) defined historically by clinical and histological features. GPA and MPA are heterogeneous entities with overlapping phenotypes. To identify novel subgroupings, cluster analysis was used to explore the phenotypic spectrum of AAV. METHODS: This study used a dataset of patients newly diagnosed as having GPA and MPA enrolled in five clinical trials. One cluster model included nine clinical baseline variables as input variables, and a second cluster model additionally included ANCA specificities. The clustering process involved multiple correspondence analyses followed by hierarchical ascendant cluster analysis. The clinical relevance of the generated clusters was analysed by their summary characteristics and outcomes. RESULTS: The analyses involved data for 673 subjects: 396 (59%) with GPA and 277 (41%) with MPA. Both cluster models resulted in five partially redundant clusters of subjects, and the model including ANCA resulted in more pertinent separations. These clusters were named 'renal AAV with proteinase 3 (PR3)-ANCA' (40% of subjects), 'renal AAV without PR3-ANCA' (32%) and 'non-renal AAV' (12%), 'cardiovascular AAV' (9%) and 'gastrointestinal AAV' (7%). The five clusters had distinct death and relapse rates. On the basis of 4 variables, 651 subjects (97%) could be accurately allocated to 1 of the 5 classes. CONCLUSIONS: This analysis suggests that AAV encompasses five classes associated with different outcomes. As compared with the traditional GPA-MPA separation, this classification system may better reflect the phenotypic spectrum of AAV.

Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To determine the association between characteristics at diagnosis and the time to first relapse in a large cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We studied long-term followup data from 4 clinical trials that included newly diagnosed patients with a broad spectrum of AAV severity and manifestations. Patient and disease characteristics at baseline were used in competing risk regression models with relapse as the event of interest and death as the competing event. RESULTS: We assessed 535 patients with 1,804 patient-years at risk of relapse. At diagnosis, the median age was 60.7 years (interquartile range [IQR] 48.8-69.1 years), 284 patients (53%) had granulomatosis with polyangiitis (Wegener's), and the median creatinine level was 203 µmoles/liter (IQR 97-498). A total of 201 patients (38%) experienced a relapse and 133 patients (25%) died, 96 of whom had not had prior relapse. Anti-proteinase 3 antibodies (subhazard ratio [sHR] 1.62 [95% confidence interval 1.39-1.89]) and cardiovascular involvement (sHR 1.59 [95% confidence interval 1.07-2.37]) were independently associated with a higher risk of relapse. Compared with patients with a creatinine level ≤100 µmoles/liter, patients with higher creatinine levels had a lower risk of relapse (sHR 0.81 [95% confidence interval 0.77-0.85] for a creatinine level of 101-200 µmoles/liter; sHR 0.39 [95% confidence interval 0.22-0.69] for a creatinine level >200 µmoles/liter). CONCLUSION: Relapse of disease is common for patients with AAV. A creatinine level >200 µmoles/liter at the time of diagnosis is strongly associated with a reduced risk of relapse and may help guide monitoring and treatment of patients with AAV.

Brief Report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Duration of relapse-free survival was longer among CYC-treated patients than among MTX-treated patients during short-term followup. The aim of the present study was to describe the long-term outcome in patients enrolled in the randomized clinical trial. METHODS: Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC-treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse-free survival, mortality, and occurrence of other clinical events. RESULTS: The median duration of followup was 6 years (range 0.1-10.8 years). One patient developed end-stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse-free survival tended to be lower in the MTX group (P = 0.056). CONCLUSION: In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long-term followup. However, first-line treatment with MTX was associated with less effective disease control than CYC-based induction therapy.

Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up.

INTRODUCTION: The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study. METHODS: Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised. RESULTS: Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs. DISCUSSION: Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

[Patients with IgA nephropathy often develop terminal uraemia]. / Patienter med IgA-nefropati utvecklar ofta terminal njursvikt.

IgA nephropathy is the most common form of inflammatory kidney disease causing uraemia world-wide and initially often a silent disease with microscopic haematuria as the only clinical finding. If left untreated, progress to terminal uraemia and dialysis is not uncommon as at least 30 % develop end stage renal failure. Awareness of the existence of the disease among GPs, internists and urologists may be helpful, not disregarding microscopic haematuria, particularly in combination with albuminuria or finding of renal casts in the urine, especially in younger individuals. No diagnostic marker in blood or urine for the disease has yet been established so kidney biopsy is still needed to confirm diagnosis. The degree of renal dysfunction, hypertension, albuminuria, and histology findings at time of diagnosis have significant impact on renal outcome. Potential biomarkers for progressive disease have been described but no one has so far been implicated in clinical practice. Until now, the only evidence-based medication consists of blockers of the renin-angiotensin-system and corticosteroids. However, new and potentially more specific drugs are under clinical investigation. Early intervention is mandatory to prevent disease progression. Thus, we want to alarm other specialists to an increased alertness for this disease, referring patients at an early stage of possible IgA nephropathy to the nephrologist for diagnosis and interventions.

The Sound of Interconnectivity; The European Vasculitis Society 2022 Report.

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.