ANCA-associated vasculitis : studies on clinical presentation and factors involving disease activity and outcome

Aims. The aim of this study was to investigate the factors associated with long-term prognosis and disease activity in patients with anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitis (AAV). An additional aim was to define the coagulation and fibrinolysis profile of renal AAV patients. Methods. Four cohorts including patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and renal-limited AAV were investigated to achieve these aims. Long-term prognosis and relapses were assessed retrospectively in a Finnish cohort of 85 patients with renal biopsy-proven AAV from a single centre (Study I). The associations between chronic nasal Staphylococcus aureus carriage (CNSAC) and proteinase 3 (PR3) ANCA with relapse were studied in AAV patients who participated in two randomised controlled trials in Europe. To define nasal CNSAC status, monthly nasal swabs were obtained from 200 patients with early systemic or generalised disease during the 18-month trials. The patient was defined as a chronic carrier of Staphylococcus aureus (S. aureus) when ≥ 75% of at least four nasal cultures were positive for S. aureus (Study II). PR3-ANCA levels, which were examined via nine different enzyme-linked immunosorbent assays (ELISAs), were obtained monthly during the 18-month trial in 28 patients with early systemic GPA. PR3-ANCA peaks were identified by the highest sum of logarithmic transformation values from all assays (Study III). The coagulation profile was assessed prospectively in 21 Finnish patients with renal AAV in the active versus the remission phase of disease and further compared with that of 40 patients with other renal diseases. The laboratory analysis consisted of platelet count, thrombin time, antithrombin activities, fibrinogen, factor VIII activity (FVIIIC), von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo), prothrombin fragments (F 1 + 2), D-dimer and antiphospholipid antibodies (Study IV). Results. The 5-year and 20-year patient survival rates were 88% and 45%, respectively. Older age and presence of myeloperoxidase (MPO) ANCA were significantly associated with worsened survival. The 5-year and 20-year renal survival rates were 79% and 68%, respectively. Renal survival was best in a focal class and worst in the sclerotic class of AAV glomerulonephritis. Female sex was significantly associated with better renal survival, while a glomerular filtration rate <30 ml/min and MPO-ANCA predicted worse renal survival. Relapse-free survival at 5 years was 47% while at 20 years it was only 10%. Patients with GPA had higher relapse risk compared with MPA patients. (Study I). The frequency of CNSAC was 12% in the whole cohort. CNSAC was almost exclusively seen in GPA patients. In patients with generalised GPA, the association with CNSAC and relapse was observed. Also, in early systemic GPA, in those patients who were under immunosuppressive treatment, a similar trend for significant association was found (Study II). A PR3-ANCA peak corresponded to relapse. However, the PR3-ANCA peak could also be identified in non-relapsing patients, and large overlaps in PR3-ANCA values prevented drawing a distinction between relapsing patients and non-relapsing patients. The alterations of immunosuppression were reflected in PR3-ANCA levels (Study III). F 1 + 2 and D-dimer were substantially elevated during active disease. During remission, their levels decreased considerably, even though D-dimer levels remained above the reference value. FVIIIC, VWF:Ag and VFW:RCo levels were high during active AAV and remained elevated during remission. The load of coagulopathies during remission was comparable to that of patients with other renal diseases involving at least moderate renal impairment. No antiphospholipid antibodies were found. Among AAV patients, two thromboembolic complications were observed (Study IV). Conclusions. In a long-term follow-up cohort, patient and renal survival were comparable with recent studies showing improved prognosis as compared to earlier reports. Both patient and renal survival were negatively predicted by the presence of MPO-ANCA. The development of end-stage renal disease was more common in men. In the long run, relapses were common, especially in patients with GPA. One special subgroup of individuals who were more prone to relapse among GPA patients were those with CNSAC. PR3-ANCA levels were not only affected by disease activity but also reflected the level of immunosuppressive treatment. Active renal AAV was characterised by enhanced coagulation and fibrinolysis, which failed to normalise completely during remission.