Objective. To estimate the incidence of and survival rates for WG, microscopic polyangiitis (MPA), Churg–Strauss syndrome (CSS) and PAN within a defined population in southern Sweden. Methods. Cases ...were retrieved using hospital records and a serology database. All new cases of WG, MPA, CSS and PAN between 1997 and 2006 were included, provided they met pre-defined criteria, and were followed until 30 June 2008. The study area comprised two health care districts with a total population of 641 000. The standardized mortality ratio (SMR) was estimated using Swedish population data as a reference. Results. A total of 140 (WG, 63; MPA 65; CSS 6; and PAN 6) cases (52% women) with a median age of 67.6 (range 20–96) years fulfilled the inclusion criteria. The annual incidence per million of the population (95% CI) was estimated to be 9.8 (7.4–12.2) for WG, 10.1 (7.7–12.6) for MPA and 0.9 (0–1.7) for both CSS and PAN. The highest incidence was found in patients aged ⩾75 years (79.1/million). The 1- and 5-year survival rates were 87.8 and 71.6% for all patients, but lower for MPA (80 and 55%) compared with WG (95 and 83%; P = 0.001), although the difference was not significant in the multivariate analysis. The SMR was 2.77 (95% CI 2.02, 3.71) for all patients. Conclusions. The incidence of WG and MPA was equal in our district, but there was a difference in survival rates related to age and renal function. A progressive increase in age-specific incidence rates was observed.
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).
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.
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%).
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.
Wegener's granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of ...patients with ANCA associated vasculitis treated with current regimens is uncertain.
To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease.
Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models.
The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate <15 ml/min, advancing age, higher Birmingham Vasculitis Activity Score, lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival.
Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.
A standard glucocorticoid regimen plus rituximab was not superior to standard intravenous cyclophosphamide as induction therapy in patients with newly diagnosed antineutrophil cytoplasmic antibody ...(ANCA)-associated vasculitis and renal involvement. Rates of sustained remission were high in both groups.
A standard glucocorticoid regimen plus rituximab was not superior to standard intravenous cyclophosphamide as induction therapy in patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and renal involvement.
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, including Wegener's granulomatosis and microscopic polyangiitis, is a multisystem autoimmune syndrome characterized by vasculitis predominantly affecting microscopic vessels and circulating autoantibodies to neutrophil cytoplasmic antigens. Renal involvement occurs in 70% of affected patients and is manifested as rapidly progressive glomerulonephritis with pauci-immune necrotizing, crescentic glomerulonephritis on biopsy. The current standard of care for ANCA-associated vasculitis is cyclophosphamide with high-dose glucocorticoids
1–4
; such regimens are effective in 70 to 90% of patients. However, cyclophosphamide is associated with leukopenia, severe infections, cancer, and ovarian failure.
5
Mortality at 1 year exceeds 15%; infection and active vasculitis are . . .
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.
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.
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.
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.
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.
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.
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.
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.
ABSTRACT
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.
Graphical Abstract
Graphical Abstract
Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in ...optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). It is unclear whether persistent ANCA when starting maintenance therapy increases the risk of ...relapse. We examined the association between ANCA status and relapse in two randomised controlled trials.
ANCA-positive patients in two trials, CYCLOPS and IMPROVE, were switched from cyclophosphamide to maintenance therapy after achieving clinical remission. We classified patients as being either ANCA-positive or ANCA-negative at the time they started maintenance therapy. We compared the risk of relapse in ANCA-positive and ANCA-negative patients.
Of 252 patients included, 102 (40%) experienced at least one relapse during the follow-up period. At the time of the switch from induction to maintenance therapy, 111 were ANCA-positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA-negative, of whom 47 (33%) relapsed. In multivariable time-to-event analysis, a reduced risk of relapse was associated with having become ANCA-negative at the time of switching to maintenance therapy (hazard ratio 0.63, 95% confidence interval 0.42-0.95; p = 0.026). In addition, initial proteinase 3 (PR3)-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction, and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse.
Becoming ANCA-negative before the switch to maintenance is associated with a reduced risk of relapse.
CYCLOPS: ClinicalTrials.gov, NCT00430105 . Registered retrospectively on 31 January 2007.
ClinicalTrials.gov, NCT00307645 . Registered retrospectively on 27 March 2006.
Abstract
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.
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