Abstract: Forty studies (3764 patients) were included. Studies conducted earlier tended to have a higher risk of bias due to poor (or poorly reported) study design, broad inclusion criteria, less well developed disease definitions and low patient numbers. Later studies tend to have improved in all areas of quality, aided by the development of large international study groups. Induction therapy: Plasma exchange as adjunctive therapy may reduce the need for dialysis at three (2 studies: RR 0.43, 95% CI 0.23 to 0.78; I2 = 0%) and 12 months (6 studies: RR 0.45, 95% CI 0.29 to 0.72; I2 = 0%) (low certainty evidence). Plasma exchange may make little or no difference to death, serum creatinine (SCr), sustained remission or to serious or the total number of adverse events. Plasma exchange may increase the number of serious infections (5 studies: RR 1.26, 95% CI 1.03 to 1.54; I2 = 0%; low certainty evidence). Remission rates for pulse versus continuous cyclophosphamide (CPA) were equivalent but pulse treatment may increase the risk of relapse (4 studies: RR 1.79, 95% CI 1.11 to 2.87; I2 = 0%) (low certainty evidence) compared with continuous cyclophosphamide. Pulse CPA may make little or no difference to death at final follow-up, or SCr at any time point. More patients required dialysis in the pulse CPA group. Leukopenia was less common with pulse treatment; however, nausea was more common. Rituximab compared to CPA probably makes little or no difference to death, remission, relapse, severe adverse events, serious infections, or severe adverse events. Kidney function and dialysis were not reported. A single study reported no difference in the number of deaths, need for dialysis, or adverse events between mycophenolate mofetil (MMF) and CPA. Remission was reported to improve with MMF however more patients relapsed. A lower dose of steroids was probably as effective as high dose and may be safer, causing fewer infections; kidney function and relapse were not reported. There was little of no difference in death or remission between six and 12 pulses of CPA. There is low certainty evidence that there were less relapses with 12 pulses (2 studies: RR 1.57, 95% CI 0.96 to 2.56; I2 = 0%), but more infections (2 studies: RR 0.79, 95% CI 0.36 to 1.72; I2 = 45%). One study reported severe adverse events were less in patients receiving six compared to 12 pulses of CPA. Kidney function and dialysis were not reported. There is limited evidence from single studies about the effectiveness of intravenous immunoglobulin, avacopan, methotrexate, immunoadsorption, lymphocytapheresis, or etanercept. Maintenance therapy: Azathioprine (AZA) has equivalent efficacy as a maintenance agent to CPA with fewer episodes of leucopenia. MMF resulted in a higher relapse rate when tested against azathioprine in remission maintenance. Rituximab is an effective remission induction and maintenance agent. Oral co-trimoxazole did not reduce relapses in granulomatosis with polyangiitis. There were fewer relapses but more serious adverse events with leflunomide compared to methotrexate. There is limited evidence from single studies about the effectiveness of methotrexate versus CPA or AZA, cyclosporin versus CPA, extended versus standard AZA, and belimumab. Plasma exchange was effective in patients with severe AKI secondary to vasculitis. Pulse cyclophosphamide may result in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst CPA is standard induction treatment, rituximab and MMF were also effective. AZA, methotrexate and leflunomide were effective as maintenance therapy. Further studies are required to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.

Plain-language summary: Forty studies (3764 patients) were identified. Plasma exchange reduces the risk of end-stage kidney disease in patients presenting with severe acute kidney failure (AKI). The use of pulse cyclophosphamide results in good remission rates but there was an increased risk of relapse. Other appropriate induction agents include rituximab and mycophenolate. Azathioprine is effective as maintenance therapy once remission has been achieved. A lower dose of steroids is just as effective as high dose and may be safer, causing fewer infections. One study shows that a new complement inhibitor can be used to replace steroids in the initial treatment of vasculitis. These are early data. The drug is likely to be very expensive so its place in treatment is not yet clearly defined. Mycophenolate mofetil has also been tested in maintenance treatment and was found to result in a higher rate of disease relapse, when compared to Azathioprine. Methotrexate and leflunomide are useful in maintenance therapy but their relative effectiveness are not clearly defined. Patients on immunosuppression for up to four years after diagnosis have a lowered relapse rate to those in whom treatment is ceased by three years. Plasma exchange was effective in patients with severe AKI. Pulse cyclophosphamide may result in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst cyclophosphamide is used as standard induction treatment, rituximab and mycophenolate mofetil were also effective. Lower dose steroids can now be safely used in initial treatment protocols. Azathioprine, rituximab, mycophenolate, methotrexate and leflunomide are effective maintenance therapy. More trials are required to understand these drugs and new therapies for quickly treating renal vasculitis.