Interventions for renal vasculitis in adults

Giles D Walters; Narelle S Willis; Tess E Cooper; Jonathan C Craig

doi:10.1002/14651858.CD003232.pub4

. 2020 Jan 13;2020(1):CD003232. doi: 10.1002/14651858.CD003232.pub4

Interventions for renal vasculitis in adults

Giles D Walters ^1,^✉, Narelle S Willis ^2,³, Tess E Cooper ³, Jonathan C Craig ^3,⁴

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6956643 PMID: 31927782

Abstract

Background

Renal vasculitis presents as rapidly progressive glomerulonephritis and comprises of a group of conditions characterised by acute kidney injury (AKI), haematuria and proteinuria. Treatment of these conditions involve the use of steroid and non‐steroid agents in combination with plasma exchange. Although immunosuppression overall has been very successful in treatment of these conditions, many questions remain unanswered in terms of dose and duration of therapy, the use of plasma exchange and the role of new therapies. This 2019 publication is an update of a review first published in 2008 and updated in 2015.

Objectives

To evaluate the benefits and harms of any intervention used for the treatment of renal vasculitis in adults.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 21 November 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

Randomised controlled trials investigating any intervention for the treatment of renal vasculitis in adults.

Data collection and analysis

Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes or mean difference (MD) for continuous outcomes.

Main results

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.

Authors' conclusions

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

Interventions for renal vasculitis in adults

What is the issue?  Renal vasculitis is a rapidly progressing form of kidney disease that causes damage to the small structures (glomeruli) inside the kidneys that help filter waste and fluids from blood to form urine. The disease means a rapid loss of kidney function. Steroids and cyclophosphamide are recommended to help suppress the immune system.

What did we do?  We searched the Cochrane Kidney and Transplant Register of Studies up to 21 November 2019 for randomised controlled trials investigating any intervention for the treatment of renal vasculitis in adults.

What did we find?  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.

Conclusions  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.

Summary of findings

Background

Description of the condition

Renal vasculitis presents as rapidly progressive glomerulonephritis (RPGN) which comprises of a group of conditions characterised by acute kidney injury (AKI), haematuria and proteinuria. Histological examination of the kidney reveals severe inflammation in the form of crescent formation, glomerular necrosis and vasculitis of small and medium sized vessels within the kidney. These conditions include the anti‐neutrophil cytoplasmic antibody (ANCA) associated vasculitides, anti‐glomerular basement membrane (anti‐GBM) disease and idiopathic RPGN (Savage 1997). ANCA‐associated vasculitides are generally small vessel vasculitides and include granulomatosis with polyangiitis (GPA; previously called Wegener's granulomatosis (WG)), microscopic polyangiitis (MPA) and renal‐limited vasculitis (Seo 2004). GPA is characterised by granulomatous inflammation usually involving the sinuses, lungs and kidneys. It is usually associated with the detection of cytoplasmic‐ANCA (c‐ANCA) specific for proteinase‐3 (PR3) in the serum of the patient (Jennette 2003). MPA is a small to medium vessel vasculitis in the presence of perinuclear‐ANCA (p‐ANCA) specific for myeloperoxidase (MPO). Studies often include GPA, MPA and renal‐limited vasculitis together as ANCA‐associated vasculitides though there is some evidence that they have distinct genetic backgrounds and therefore pathogenesis (Lyons 2012). Eosinophilic GPA is also classified as an ANCA‐associated vasculitides (Jennette 2013), but is not specifically included in this review. In the majority of studies, it is excluded. It is a less well defined condition with overlap with other eosinophilic diseases. Evidence increasingly points to the pathogenicity of ANCA (Jennette 2008). Other conditions also cause vasculitis in the kidney such as Henoch Schonlein Purpura and cryoglobulinaemia resulting in immune deposits visible on electron microscopic examination of renal tissue. The treatment of Goodpasture's disease and other forms of RPGN with granular immune deposits (which have an entirely separate pathogenesis to the pauci‐immune (no immune deposits) forms of the disease) has not been addressed in this review.

Description of the intervention

Treatments for vasculitis involve suppression of the immune system and have been highly successful. Death of untreated vasculitis was 80% at one year (Phillip 2008). Recent figures suggest 80% five‐year survival with modern immunosuppression (Harper 2011). Induction protocols have historically been based around the use of cyclophosphamide (CPA), either daily oral dosing or monthly intravenous (IV) pulses (Bolton 1989; Savage 1997). More recently anti‐CD20 monoclonal antibody treatment has gained some popularity as a primary treatment, though supported by a considerably smaller body of evidence. In the presence of kidney failure, plasma exchange is often used as an adjunct to pharmacological treatment (Lockwood 1976; Pusey 1991; Rondeau 1989). Once remission of the disease is achieved, treatment is scaled back with lower doses of steroids and the induction agent is replaced by a less potent immunosuppressive, such as azathioprine (AZA). Co‐trimoxazole has been used in GPA mainly to prevent the occurrence of pneumocystis infection, upper respiratory tract infection and subsequent relapse of disease. Various guidelines are available which summarise available treatment options and some of the evidence for their use (Lapraik 2007; Menahem 2008; Mukhtyar 2009).

How the intervention might work

There are multiple interventions deployed in this condition. The majority of these interventions work by suppression of the immune system in various ways. Some of these are well defined whereas others are not. For instance, rituximab works by specifically binding to CD20 a molecule expressed on B cell subsets. It works to inhibit the actions of these cells and reduce levels of antibodies that are thought to be pathogenic in this disease. CPA also is directed against B cells. AZA is an anti‐metabolite which inhibits cell proliferation and tends to inhibit lymphocytes, since they have a high rate of cell division. Steroids, also known as glucocorticoids, have a broad immunosuppressive effect via multiple cellular pathways.

Why it is important to do this review

These treatments are well established but many questions remain unanswered. Though recent guidelines are comprehensive (KDIGO 2012), optimal agent, dose, duration, route and frequency of treatment are uncertain. CPA can be given as a daily oral dose or in intermittent oral or IV doses (Adu 1997). IV regimens tend to give a lower total dose and have fewer side effects, but give a higher rate of relapse (de Groot 2001; Harper 2011). Treatment may also include IV methylprednisolone or plasma exchange but their place in therapy is debated (Kerr 2001; Levey 1994). Other therapies including mycophenolate mofetil (MMF), anti‐TNF alpha therapy, leflunomide, methotrexate (MTX), anti‐adhesion molecule (CD52) therapy and IV immunoglobulin (IVIg) have been suggested (Jayne 2000a; Nowack 1997; Tervaert 2001) but the randomised controlled trial (RCT) data are limited.

Death from this condition remains significant with more than 10% of patients with severe ANCA‐associated vasculitides dying in the first 12 months after diagnosis (Little 2010). Fifty percent of these are caused by treatment side effects.

Objectives

To evaluate the benefits and harms of any intervention used for the treatment of renal vasculitis in adults.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at any intervention used for the treatment of renal vasculitis in adults.

Types of participants

Inclusion criteria

All adult patients suffering from vasculitis with renal involvement. Renal involvement includes an episode of AKI, proteinuria and haematuria, or both, with a kidney biopsy showing severe acute glomerulonephritis with crescents, glomerular necrosis or other histological evidence of vasculitis or a positive test for ANCA antibodies. AKI was defined by the included studies.

Exclusion criteria

RPGN with granular immune deposits such as systemic lupus erythematosus, cryoglobulinaemia, Henoch‐Schonlein Purpura
RPGN secondary to infections
Polyarteritis nodosa (PAN)
Eosinophilic GPA
Goodpasture's disease (or anti‐GBM antibody disease).

Types of interventions

Any pharmacological intervention covering:

Corticosteroids versus placebo
Non‐corticosteroid agents, including CPA, AZA, plasma exchange and immunoadsorption, with or without concurrent use of other immunosuppressive agents
Different doses and duration of corticosteroid treatment
Different doses, duration and route of administration of non‐corticosteroid treatment
Any other agents evaluated in an RCT.

Types of outcome measures

Primary outcomes

Death at 1, 2 and 5 years
Kidney function: serum creatinine (SCr), glomerular filtration rate (GFR) at 1, 2, 3, 6 and 12 months then annually
Need for kidney replacement therapy (KRT) at 1, 2, 3, 6 and 12 months then annually.

Secondary outcomes

Number of patients achieving remission
Number of patients relapsing (as defined by the study)
Adverse effects of each drug (e.g. nausea, leukopenia, infections)
Cumulative doses of steroid and other agents.

Relapse of disease was defined by the included studies, but typically included an increase in Birmingham Vasculitis Activity Score (BVAS) score or a recurrence of symptoms of vasculitis.

Search methods for identification of studies

Electronic searches

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Searches of kidney and transplant journals, and the proceedings and abstracts from major kidney and transplant conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Reference lists of review articles, relevant studies and clinical practice guidelines.
Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that did not meet inclusion criteria although studies and reviews that might include relevant data or information on studies were retained initially. Two authors independently assessed abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out by the same authors independently using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study exists, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions those data were used.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (seeAppendix 2).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
Were incomplete outcome data adequately addressed (attrition bias)?
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

Dichotomous outcomes were expressed as a risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment, the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales had been used.

The summary measure data were translated into number needed to treat (NNT) and number needed to harm (NNH) for the observed overall baseline risks. Adverse effects were tabulated and assessed with descriptive techniques. The risk differences with 95% CI were to be calculated for each adverse effect, either compared to no treatment or compared to another agent, unfortunately there were insufficient studies to do this.

Dealing with missing data

Any further information required from the original author was requested by written correspondence and any relevant data obtained in this manner were included in the review.

Assessment of heterogeneity

For this update we first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows:

0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a CI for I²) (Higgins 2011).

Assessment of reporting biases

Although we planned to construct funnel plots to assess for the potential existence of small study bias, we did not identify sufficient studies to enable analysis (Higgins 2011).

Data synthesis

Data were pooled using the random effects model but the fixed effects model were also analysed to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Because there were insufficient studies comparing the same pair of interventions we were unable to explore whether there were differences in the following study level characteristics; participants (age, gender and kidney function at presentation), treatments and study quality variability The review reports the therapeutic agent used, its dose and duration of therapy.

'Summary of findings' tables

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the certainty of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The certainty of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). Two review authors independently rated the certainty of the evidence for each outcome. We used the GRADE system to rank the certainty of the evidence using the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). See Appendix 3 for steps for assessing GRADE and reasons for upgrading or downgrading the certainty of the evidence. We presented the following outcomes in the 'Summary of findings' tables:

Death (one year; end of study; end of follow‐up)
Kidney function (one year; end of study; end of follow‐up)
Dialysis (one year; end of study)
Remission (induction only; six months; one year)
Relapse (any time point)
Serious adverse events (e.g. causing death or study drug discontinuation)
Infections (serious; any).

Results

Description of studies

Results of the search

A PRISMA flow chart combining all searches and screening results is shown in Figure 1.

For this 2019 update, we searched the Cochrane Kidney and Transplant Specialised Register up to November 2019. Since 2008, inclusive of all updates of this review, we have identified a total of 4170 reports and examined 63 full‐text studies (267 reports). We included 40 studies (226 reports) (see Included studies). We have excluded seven studies (11 reports) (Basu 2017; CHUSPAN 2 2017; De Vita 2012; Harper 2018; Imai 2006; Ribi 2010; Rifle 1990), six studies (eight reports) are awaiting classification (Chen 2011c; CLASSIC 2016; Henderson 2009; MAINTANCAVAS 2017; Pagnoux 2003; RATTRAP 2015), and ten studies (22 reports) are ongoing (ADVOCATE 2019; ALEVIATE 2018; CANVAS 2016; COMBIVAS 2019; MAINRITSAN 3 2015; MUPIBAC 2004; NCT03323476; RITAZAREM 2013; Tuin 2019).

Included studies

Forty studies (3764 participants) were included in this review. See Characteristics of included studies. Nine new studies have been included since the 2015 update.

Types of treatments for remission induction

Plasma exchange adjunctive therapy (Cole 1992; Glockner 1988; Mauri 1985; MEPEX 2007; PEXIVAS 2013; Pusey 1991; Rifle 1980; Szpirt 2011; Zauner 2002)
Pulse versus continuous CPA treatment (Adu 1997; CYCLOPS 2004; Guillevin 1997; Haubitz 1998)
Ten studies considered other potential treatments including: rituximab (RAVE 2010; RITUXVAS 2010), mycophenolate mofetil (Han 2011b; Hu 2008b; MYCYC 2012), methotrexate (NORAM 2005), avacopan (CLEAR 2013), intravenous immunoglobulin for refractory disease (Jayne 2000), immunoadsorption (Stegmayr 1999), lymphocytapheresis (Furuta 1998)
Six to 12 pulses of CPA for vasculitis with poor prognostic factors (Guillevin 2003; CORTAGE 2015)
Reduced dose to standard dose of steroids (PEXIVAS 2013)
Etanercept and placebo (WGET 2002).

As the inclusion and exclusion criteria and treatment regimens varied so widely they have been listed in separate tables (see Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9).

Types of maintenance therapies

Maintenance treatment was considered by sixteen studies including comparisons of:

Azathioprine after three months of remission induction with continued cyclophosphamide (CYCAZAREM 2003);
Azathioprine and mycophenolate mofetil (IMPROVE 2003)
Azathioprine and methotrexate (WEGENT 2008)
Azathioprine and rituximab (MAINRITSAN 2014)
Co‐trimoxazole and placebo (Stegeman 1996; Zycinska 2009)
Cyclosporin and cyclophosphamide (Szpirt 2011)
Extended and standard azathioprine (AZA‐ANCA 2016; REMAIN 2003)
Methotrexate and leflunomide (Metzler 2007)
Methotrexate and cyclophosphamide (Maritati 2017)
Tailored and fixed rituximab (MAINRITSAN 2 2018)
Pre‐emptive therapy for relapse (Boomsma 2003; Tervaert 1990)
Belimumab with placebo (BREVAS 2019).

As the inclusion and exclusion criteria and treatment regimens varied so widely they have been listed in separate tables (see Appendix 10; Appendix 11).

No quasi‐RCTs were identified.

Diagnoses

The vast majority of the studies included patients now recognised as having ANCA‐associated vasculitis in the forms of GPA, MPA and renal‐limited vasculitis.

Other included diagnoses were mainly in earlier studies and included extracapillary and endo‐extracapillary proliferative GN (Rifle 1980), Goodpasture's disease (Stegmayr 1999; only 6/52 patients had this diagnosis), lymphomatoid granulomatosis (Mauri 1985), necrotizing angiitis (Mauri 1985), post‐infectious disease RPGN (Cole 1992), PAN (Adu 1997; Glockner 1988; Mauri 1985), scleroderma (Glockner 1988), and systemic lupus erythematous (Glockner 1988).

Excluded studies

Seven studies have been excluded, five due to the wrong participant population to fit our criteria (CHUSPAN 2 2017; De Vita 2012; Imai 2006; Ribi 2010; Rifle 1990), and two studies were not induction or maintenance studies (Basu 2017; Harper 2018). See Characteristics of excluded studies.

Non‐RCTs have been removed from this review update (Figure 1).

Risk of bias in included studies

For a summary of the risk of bias assessments see Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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 transnational study groups.

Allocation

Random sequence generation

Randomisation methods were not clearly reported in 13 studies (Boomsma 2003; Furuta 1998; Guillevin 1997; Haubitz 1998; Hu 2008b; Mauri 1985; Pusey 1991; Rifle 1980; Stegmayr 1999; Tervaert 1990; WGET 2002; Zauner 2002; Zycinska 2009).

Randomisation methods were adequately reported in the remaining 27 studies. Such methods included:

Computer‐generated random numbers and stratified for kidney function, urine volume, and by country and disease;
Stratified for oliguria or dialysis;
Stratified by disease severity and by recruiting centre;
Telephone with a statistician;
Stratified by hospital;
Stratified for diagnosis; and centrally performed.

Allocation concealment

Allocation concealment was not performed in Maritati 2017, (high risk). Allocation concealment was unclear in 18 studies (Boomsma 2003; Cole 1992; CORTAGE 2015; Furuta 1998; Guillevin 1997; Guillevin 2003; Han 2011b; Haubitz 1998; Hu 2008b; Mauri 1985; Metzler 2007; Pusey 1991; REMAIN 2003; Rifle 1980; Stegmayr 1999; Tervaert 1990; Zauner 2002; Zycinska 2009), and at low risk of bias for the remaining 21 studies (Adu 1997; AZA‐ANCA 2016; BREVAS 2019; CLEAR 2013; CYCAZAREM 2003; CYCLOPS 2004; Glockner 1988; IMPROVE 2003; Jayne 2000; MAINRITSAN 2014; MAINRITSAN 2 2018; MEPEX 2007; MYCYC 2012; NORAM 2005; PEXIVAS 2013; RAVE 2010; RITUXVAS 2010; Stegeman 1996; Szpirt 2011; WEGENT 2008; WGET 2002).

Blinding

Performance bias

Five studies provided adequate descriptions of blinding both the participants and study personnel (BREVAS 2019; CLEAR 2013; Jayne 2000; Stegeman 1996; WGET 2002) (low risk of performance bias). For 22 studies, blinding of participants or study personnel was not possible however the risk of bias was judged to be low as this was unlikely to affect the outcomes of the studies (Adu 1997; Boomsma 2003; CYCLOPS 2004; Glockner 1988; Guillevin 1997; Guillevin 2003; Han 2011b; Haubitz 1998; Hu 2008b; IMPROVE 2003; MEPEX 2007; Metzler 2007; MYCYC 2012; NORAM 2005; Pusey 1991; Rifle 1980; RITUXVAS 2010; Stegmayr 1999; Szpirt 2011; Tervaert 1990; WEGENT 2008; Zauner 2002). Cole 1992 blinded the participants and review of the initial biopsies (low risk).

Blinding or participants or investigators could not be determined in five studies and judged to be an unclear risk (CYCAZAREM 2003; Furuta 1998; Mauri 1985; RAVE 2010; Zycinska 2009).

Six studies were open‐label and the methods used were judged to be high risk (AZA‐ANCA 2016; CORTAGE 2015; MAINRITSAN 2014; MAINRITSAN 2 2018; Maritati 2017; PEXIVAS 2013; REMAIN 2003).

Detection bias

BREVAS 2019 was judged to be low risk for adequately blinding all outcome assessors.

In 32 studies there was a lack of information regarding blinding of the outcome assessors and judged to be unclear risk. Cole 1992 blinded the review of the final biopsies and Stegeman 1996 blinded the participant's physician. In CYCLOPS 2004 outcomes were classified by non‐blinded investigators and validated by an independent observer. Two studies had centralised computer entry from data books (CYCAZAREM 2003; CYCLOPS 2004). For the rest of the studies no further information was reported.

Seven studies reported a clear indication that the outcome assessors were not blinded and judged to be high risk (AZA‐ANCA 2016; CORTAGE 2015; MAINRITSAN 2014; MAINRITSAN 2 2018; Maritati 2017; MYCYC 2012; PEXIVAS 2013).

Incomplete outcome data

The completeness of follow‐up ranged from 82% to 100%. In most studies follow‐up was generally good with few patients being lost to follow‐up or being withdrawn from the studies.

Thirty‐two studies were judged to be at low risk of attrition bias. Four studies were judged unclear risk due to insufficient details to judge (BREVAS 2019; MYCYC 2012; REMAIN 2003; Rifle 1980), and four studies were judged to be at high risk due to either high attrition rates, or too many missing participants who were not accounted for at the end of the trials (Haubitz 1998; Hu 2008b; Mauri 1985; Metzler 2007).

Selective reporting

Selective reporting bias was generally not detected. These were mostly small studies with very limited reporting measures. The larger studies had very clearly defined outcomes which were clearly reported.

Twenty‐seven studies were judged to be low risk of reporting bias. Eight studies were judged to be unclear risk (Cole 1992; CORTAGE 2015; Glockner 1988; Guillevin 2003; Maritati 2017; Pusey 1991; REMAIN 2003; Tervaert 1990), and five studies were judged to be at high risk of reporting bias (Boomsma 2003; Furuta 1998; Mauri 1985; Zauner 2002; Zycinska 2009).

Other potential sources of bias

Sixteen studies were judged to be at low risk of other sources of bias.

Potential biases were unclear in 11 studies (Boomsma 2003; CORTAGE 2015; Furuta 1998; Hu 2008b; Mauri 1985; PEXIVAS 2013; REMAIN 2003; Rifle 1980; Stegmayr 1999; Szpirt 2011; Zauner 2002).

Thirteen studies were judged to be at high risk of other sources of bias:

Groups appeared to be unbalanced (age, kidney function, BVAS score) (Adu 1997; BREVAS 2019; Guillevin 2003; Zycinska 2009).
Studies were terminated early (interim analyses showed increased side effects; higher rate of relapses; significant differences between the groups) (AZA‐ANCA 2016; BREVAS 2019; Guillevin 1997; Haubitz 1998; Metzler 2007).
Funded by pharmaceutical industry (BREVAS 2019; CLEAR 2013; Jayne 2000; MAINRITSAN 2 2018).
Patients crossed from one treatment arm to the other after four weeks of treatment (Glockner 1988)
Time taken to complete the study (10 years) subject to biases involved in changing physician perceptions of the efficacy of treatment (Pusey 1991).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9

Summary of findings for the main comparison. Plasma exchange as adjunctive therapy for renal vasculitis.

Plasma exchange as adjunctive therapy for renal vasculitis
Patient or population: adults with renal vasculitis  Settings: inpatients then outpatients  Intervention: plasma exchange as adjunctive therapy Comparison: standard therapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Control	Plasma exchange
Death at one year	189 per 1000	197 per 1000  (108 to 364)	RR 1.04  (0.57 to 1.92)	267 (5)	⊕⊕⊝⊝  low^1,2
Serum creatinine at 1 year	Mean serum creatinine in the plasma exchange group was 23.52 µmol/L higher (17.19 lower to 64.22 higher) than the control group		‐‐	156 (4)	⊕⊕⊝⊝  low^1,3
Dialysis at one year	376 per 1000	169 per 1000  (109 to 271)	RR 0.45   (0.29 to 0.72)	235 (6)	⊕⊕⊝⊝  low^1,2
Sustained remission	560 per 1000	571 per 1000 (498 to 649)	RR 1.02 0.89 to 1.16)	704 (1)	⊕⊕⊝⊝  low^1,2
Relapse	not reported	not reported	‐‐	‐‐	‐‐
Total number of adverse events	577 per 1000	583 per 1000 (525 to 646)	RR 1.01 (0.91 to 1.12)	956 (5)	⊕⊕⊝⊝  low^1,2
Serious infections	253 per 1000	318 per 1000  (260 to 389)	RR 1.26  (1.03 to 1.54)	956 (5)	⊕⊕⊝⊝  low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Pulse cyclophosphamide (CPA) versus continuous CPA for remission induction
Patient or population: adults with renal vasculitis  Settings: inpatients then outpatients  Intervention: pulse CPA  Comparison: continuous CPA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Continuous CPA	Pulse CPA
Death at final follow‐up	206 per 1000	158 per 1000  (90 to 271)	RR 0.77   (0.44 to 1.32)	278 (4)	⊕⊕⊝⊝  low^1,2
Serum creatinine at 12 months	Mean serum creatinine in the pulse CPA group was 9.78 µmol/L lower (53.16 lower to 33.61 higher) than the continuous CPA group		‐‐	52 (2)	⊕⊕⊝⊝  low^2,3
Dialysis at end of study	74 per 1000	140 per 1000  (68 to 288)	RR 1.90  (0.92 to 3.91)	245 (4)	⊕⊕⊝⊝  low^1,2
Remission at 6 months	880 to 1000	906 per 1000 (808 to 994)	RR 1.03 (0.93 to 1.13)	176 (2)	⊕⊕⊝⊝  low^1,2
Relapse at the end of follow‐up	181 per 1000	324 per 1000  (201 to 519)	RR 1.79   (1.11 to 2.87)	235 (4)	⊕⊕⊝⊝  low^1,2
Adverse events ‐ treatment failure	140 per 1000	190 per 1000 (21 to 1000)	RR 1.36 (0.115 to 12.56)	82 (2)	⊕⊕⊝⊝  low^1,2
Serious infections	348 per 1000	247 per 1000  (132 to 462)	RR 0.71   (0.38 to 1.33)	278 (4)	⊕⊕⊝⊝  low^1,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Rituximab compared to cyclophosphamide (CPA) for remission induction
Patient or population: adults with renal vasculitis  Settings: inpatients then outpatients  Intervention: rituximab  Comparison: CPA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	CPA	Rituximab
Death at 6 months	28 per 1000	28 per 1000 (6 to 129)	RR 1.00 (0.21 to 4.70)	241 (2)	⊕⊕⊕⊝  moderate¹
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis	not reported	not reported	‐‐	‐‐	‐‐
Remission at 6 months	661 per 1000	674 per 1000  (522 to 872)	RR 1.02  (0.79 to 1.32)	236 (2)	⊕⊕⊕⊝  moderate¹
Relapse at 12 months	100 per 1000	143 per 1000 (18 to 1000)	RR 1.43 (0.18 to 11.31)	38 (1)	⊕⊕⊝⊝  low^1,2
Serious adverse events	826 per 1000	971 per 1000 (594 to 1000)	RR 1.11 (0.72 to 1.71)	241 (2)	⊕⊕⊕⊝  moderate¹
Serious Infections	92 per 1000	82 per 1000  (39 to 176)	RR 0.89  (0.62 to 1.92)	241 (2)	⊕⊕⊕⊝  moderate³
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Mycophenolate mofetil (MMF) versus cyclophosphamide (CPA) for remission induction
Patient or population: adults with renal vasculitis  Settings: inpatients then outpatients  Intervention: MMF  Comparison: CPA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	CPA	MMF
Death at 6 months	57 per 1000	71 per 1000 (20 to 255)	RR 1.25 (0.35 to 4.46)	140 (1)	⊕⊕⊝⊝  low^1,2
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis	29 per 1000	29 per 1000 (4 to 197)	RR 1.00 (0.14 to 6.90)	140 (1)	⊕⊕⊝⊝  low^1,2
Relapse at any time point	203 per 1000	366 per 1000 (203 to 654)	RR 1.80 (1.00 to 3.22)	127 (1)	⊕⊕⊝⊝  low^1,2
Remission at 6 months	716 per 1000	837 per 1000  (723 to 966)	RR 1.17   (1.01 to 1.35)	216 (3)	⊕⊕⊕⊝  moderate³
Serious adverse events	400 per 1000	500 per 1000 (344 to 724)	RR 1.25 (0.86 to 1.81	140 (1)	⊕⊕⊝⊝  low^1,2
Infection	183 per 1000	233 per 1000 (138 to 396)	RR 1.27 (0.75 to 2.16)	216 (3)	⊕⊕⊕⊝  moderate³
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Intravenous immunoglobulin (IVIg) compared to placebo for renal vasculitis in adults
Patient or population: adults with renal vasculitis  Settings: inpatients then outpatients  Intervention: IVIg  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Placebo	IVIg
Death	118 per 1000	24 per 1000 (1 to 456)	RR 0.20 (0.01 to 3.88)	34 (1)	⊕⊕⊝⊝  low^1,2
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis	not reported	not reported	‐‐	‐‐	‐‐
Response at 3 months	353 per 1000	822 per 1000  (416 to 1000)	RR 2.33   (1.18 to 4.61)	34 (1)	⊕⊕⊝⊝  low^1,2
Relapse at 3 months	267 per 1000	312 per 1000 (104 to 949)	RR 1.17 (0.39 to 3.56)	34 (1)	⊕⊕⊝⊝  low^1,2
Adverse events	235 per 1000	706 per 1000 (285 to 1000)	RR 3.00 1.21 to 7.45)	34 (1)	⊕⊕⊝⊝  low^1,2
Serious infection	not reported	not reported	‐‐	‐‐	‐‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Azathioprine (AZA) versus cyclophosphamide (CPA) for maintenance therapy
Patient or population: adults with renal vasculitis for maintenance therapy  Settings: inpatients then outpatients  Intervention: AZA  Comparison: CPA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	CPA	AZA
Death (median follow‐up time 8.5 years)	164 per 1000	127 per 1000 (58 to 283)	RR 0.77 (0.35 to 1.72)	144 (1)	⊕⊕⊕⊝  moderate¹
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis (median follow‐up time 8.5 years)	110 per 1000	181 per 1000	RR 1.65 (0.57 to 4.79)	144 (1)	⊕⊕⊕⊝  moderate¹
Relapse at 18 months	137 per 1000	155 per 1000  (70 to 342)	RR 1.13   (0.51 to 2.50)	144 (1)	⊕⊕⊕⊝  moderate¹
Relapse (median follow‐up time 8.5 years)	356 per 1000	520 per 1000  (356 to 762)	RR 1.46  (1.00 to 2.14)	144 (1)	⊕⊕⊕⊝  moderate¹
Serious adverse events	96 per 1000	113 per 1000 (43 to 294)	RR 1.18 (0.45 to 3.07)	144 (1)	⊕⊕⊕⊝  moderate¹
Infections	178 per 1000	183 per 1000  (91 to 367)	RR 1.03   (0.51 to 2.06)	144 (1)	⊕⊕⊕⊝  moderate¹
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Azathioprine (AZA) versus methotrexate (MTX) for renal vasculitis for maintenance therapy
Patient or population: adults with renal vasculitis for maintenance therapy  Settings: inpatients then outpatients  Intervention: AZA  Comparison: MTX
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	MTX	AZA
Death	16 per 1000	5 per 1000 (0 to 127)	RR 0.33 (0.01 to 8.03	126 (1)	⊕⊕⊝⊝  low^1,2
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis	not reported	not reported	‐‐	‐‐	‐‐
Relapse	333 per 1000	367 per 1000  (227 to 590)	RR 1.10  (0.68 to 1.77)	126 (1)	⊕⊕⊝⊝  low^1,2
Adverse events causing death or study drug discontinuation	190 per 1000	110 per 1000  (48 to 263)	RR 0.58  (0.25 to 1.38)	126 (1)	⊕⊕⊝⊝  low^1,2
Severe adverse events	175 per 1000	79 per 1000 (30 to 215)	RR 0.58 0.25 to 1.38)	126 (1)	⊕⊕⊝⊝  low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Antibiotics versus placebo for maintenance therapy
Patient or population: adults with renal vasculitis for maintenance therapy  Settings: inpatients then outpatients  Intervention: antibiotics Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Antibiotics
Death at 6 months	25 per 1000	8 per 1000 (0 to 194)	RR 0.33 (0.01 to 7.76)	81 (1)	⊕⊕⊝⊝  low¹
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis	not reported	not reported	‐‐	‐‐	‐‐
Remission at one year	796 per 1000	908 per 1000  (780 to 1000)	RR 1.14   (0.98 to 1.33)	111 (2)	⊕⊕⊝⊝  low^2,3
Relapse	not reported	not reported	‐‐	‐‐	‐‐
Adverse events causing study drug discontinuation	50 per 1000	195 per 1000 (44 to 863)	RR 3.90 (0.88 to 17.26)	81 (1)	⊕⊕⊝⊝  low¹
Infection (urinary tract infection)	25 per 1000	8 per 1000 (0 to 194)	RR 0.33 (0.01 to 7.76	81 (1)	⊕⊕⊝⊝  low¹
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Leflunomide compared to methotrexate (MTX) for maintenance therapy
Patient or population: adults with renal vasculitis for maintenance therapy  Settings: inpatients then outpatients  Intervention: leflunomide  Comparison: MTX
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	MTX	Leflunomide
Death	not reported	not reported	‐‐	‐‐	‐‐
Kidney function	not reported	not reported	‐‐	‐‐	‐‐
Dialysis	not reported	not reported	‐‐	‐‐	‐‐
Relapse	464 per 1000	232 per 1000  (102 to 515)	RR 0.50  (0.22 to 1.11)	54 (1)	⊕⊕⊝⊝  low¹
Serious adverse events*	no events	5/26*	RR 11.81 (0.69 to 203.68)	54 (1)	⊕⊕⊝⊝  low¹
Infection	429 per 1000	501 per 1000 (283 to 887)	RR 1.17 (0.27 to 106.88)	54 (1)	⊕⊕⊝⊝  low¹
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Date	Event	Description
19 December 2019	New citation required and conclusions have changed	New interventions added
19 December 2019	New search has been performed	New studies added; SoF tables added

Date	Event	Description
25 August 2015	New citation required and conclusions have changed	New interventions included
25 August 2015	New search has been performed	Multiple new studies included; methodology updated
20 March 2008	Amended	Converted to new review format.

Database	Search terms
CENTRAL	wegener* (systemic near/3 vasculitis):ti,ab,kw (Word variations have been searched) ((renal or kidney) and vasculitis):ti,ab,kw (Word variations have been searched) rapidly progressive glomeruloneph:ti,ab,kw (Word variations have been searched) glomerular* and necrosis:ti,ab,kw (Word variations have been searched) glomerular* and crescent:ti,ab,kw (Word variations have been searched) anti‐neutrophil cytoplasmic antibod or antineutrophil cytoplasmic antibod*:ti,ab,kw (Word variations have been searched) anca associated vasculitis:ti,ab,kw (Word variations have been searched) {or #1‐#8}
MEDLINE	exp Vasculitis/ Antibodies, Antineutrophil Cytoplasmic/ or/1‐2 ((renal or kidney$) and vasculitis).tw. rapidly progressive glomerulonephritis.tw. glomerular necrosis.tw. (crescent$ and glomerular$).tw. (anti‐neutrophil cytoplasmic antibod$ or antineutrophil cytoplasmic antibod$).tw. anca associated vasculitis.tw. granulomatosis with polyangiitis.tw. (systemic adj3 vasculitis).tw. or/4‐10 3 and 13
EMBASE	wegener's granulomatosis/ Rapidly progressive glomerulonephritis/ neutrophil cytoplasmic antibody/ ANCA associated vasculitis/ wegener's granulomatosis.tw. rapidly progressive glomerulonephritis.tw. (anti‐neutrophil cytoplasmic antibod$ or antineutrophil cytoplasmic antibod$).tw. ((renal or kidney$) and vasculitis).tw. glomerular necrosis.tw. (crescent$ and glomerular$).tw. (systemic adj3 vasculitis).tw. anca associated vasculitis.tw. or/1‐12

Study ID	Inclusion criteria	Exclusion criteria
Cole 1992	RPGN of undefined aetiology (idiopathic or post‐infectious disease) with specific pathologic criteria; adults (16 to 75 years); normal sized kidneys SCr > 170 μmol/L, increasing by 44 μmol/week or both; no evidence of systemic disease or anti‐GBM antibody‐induced disease; renal biopsy within 5 days of study entry	Cellular crescents in < 50% non‐obsolescent glomeruli; evidence of serious infection or active ulcer disease
Glockner 1988	RPGN with >70% crescents on kidney biopsy; CrCl < 50 mL/min; urine output >200 mL/24 h	Anti‐GBM disease; life threatening conditions; contraindications to immunosuppression; previous treatment with AZA or CPA for > 14 days
Mauri 1985	Histologically proven crescentic GN and rapidly progressive kidney impairment	< 60% glomerular involvement, primary glomerulopathies, transplanted kidneys, SLE, HSP
MEPEX 2007	Biopsy‐proven ANCA‐associated necrotizing GN with AKI (SCr > 500 μmol/L)	Aged < 18 years or > 80 years; inadequate contraception; pregnancy; previous malignancy; hepatitis B antigenaemia or hepatitis C antibody or HIV infection; other multisystem autoimmune disease; circulating anti‐GBM antibody or linear staining of GBM on histology; life‐threatening non‐renal manifestations of vasculitis; dialysis for > 2 weeks before entry; Cr > 200 µM more than 1 year before entry; > 2 weeks treatment with CPA or AZA; > 500 mg of IV MP; PE within the preceding year; > 3 months treatment with oral prednisolone; allergy to study medications
PEXIVAS 2013	New or previous clinical diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis consistent with the Chapel‐Hill consensus definitions AND positive test for proteinase 3‐ANCA or myeloperoxidase‐ANCA AND severe vasculitis defined by at least one of the following: Renal involvement with both: renal biopsy demonstrating focal necrotizing glomerulonephritis or active urine sediment characterized by glomerular haematuria or red cell casts and proteinuria AND eGFR <50 mL/min/1.73 m². Pulmonary haemorrhage due to active vasculitis defined by a compatible chest X‐ray or CT scan (diffuse pulmonary infiltrates) AND the absence of an alternative explanation for all pulmonary infiltrates (e.g. volume overload or pulmonary infection) AND At least one of the following: evidence of alveolar haemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage; observed haemoptysis. Unexplained anaemia (< 10 g/dL) or documented drop in Hb >1 g/dL); increased diffusing capacity of carbon dioxide	Diagnosis of vasculitis other than granulomatosis with polyangiitis or microscopic polyangiitis; positive anti‐glomerular basement membrane antibody test or renal biopsy demonstrating linear glomerular immunoglobulin deposition; receipt of dialysis for > 21 days immediately prior to randomisation or prior renal transplant; aged < 15 years; pregnancy; inability or unwillingness to comply with birth control/abstinence; treatment with > 1 IV dose of CPA and/or > 14 days of oral CPA and/or > 14 days of prednisone/prednisolone (> 30 mg/day) and/or >1 dose of RTX within the 28 days immediately prior to randomisation; a comorbidity that, in the opinion of the investigator, precludes the use of CPA, glucocorticoids, or PE or absolutely mandates the use of PE
Pusey 1991	Focal necrotizing GN with crescents (WG, systemic vasculitis, polyarteritis, idiopathic RPGN)	Anti‐GBM disease; SLE; HSP; chronic GN; previously treated with IV MP, oral CPA or PE
Rifle 1980	New onset RPGN with > 50% glomerular crescents	Goodpasture's syndrome; IgA nephropathies; SLE; systemic disease
Szpirt 2011	All patients with a new diagnosis of WG who were c‐ANCA or PR3‐ANCA positive; clinical manifestations as defined by Fauci 1973 from at least 2 organ systems, histology proven WG and positive ANCE by IIF and ELISA; all patients fulfilled the ACR 1990 classification for WG	Not reported
Zauner 2002	Patients with a clinical picture of RPGN and Couser Type II or III (immune deposits or pauci‐immune respectively)	Couser Type I GN (linear GBM Ab staining on biopsy), previous immunosuppression or PE

Study ID	Treatment	Control	Study outcomes
Cole 1992	Immunosuppression as for control group PE: at least 10 PE treatments within 16 days of study entry; 1 plasma volume with complete replacement using 5% albumin + crystalloid	Immunosuppression IV MP: 10 mg/kg/day for 3 days followed by prednisone 1.4 mg/kg/day for next 4 days and then tapered to 1 mg/kg/day over 2 weeks; 0.35 mg/kg/day at 1 month and 025 mg/kg/day at 2 months AZA: 1.5 to 3.0 mg/kg/day with dose adjustment as necessary to ensure neutrophil count of ≥ 2.0 x 10⁹/L	Kidney pathology Patients on dialysis at randomisation: dialysis at 1, 3, 6, 12 months Kidney function in patients not on dialysis: 1, 3, 6, 12 months Change in SCr Adverse events (serious infections, gastrointestinal bleeding) Death
Glockner 1988	PE: 9 x 50 mL/kg over 4 weeks replaced with 3% to 5% albumin solution Immunosuppression as for control group	Immunosuppression CPA (3 mg/kg/day) + AZA (1 mg/kg/day) for 1 week AZA (2 mg/kg/day) MP (1.5 mg/kg/day) for 14 days reducing in 4 mg/day steps to maintenance 8 mg/day Patients with WG (2) did not receive AZA, only CPA (3 mg/kg/day) for entire study period	Death at 6 months Dialysis at 6 months  SCr at 4 weeks, 8 weeks and 6 months  Adverse events including serious infections, GI haemorrhage and anaphylaxis
Mauri 1985	CPA and prednisolone as for control group PE alternate days for 6 treatments Exchanges of at least 3.5 L replaced with 3.5% albumin and 2 units FFP	CPA: 2 mg/kg/day Dose reduced to 0.5 mg/kg/day after 2 months then stopped after month 4 Prednisolone: 1 mg/kg/day Dose reduced to half after 8 weeks; prednisolone dose tapered progressively	Death  Dialysis post treatment, at 3 months and 12 months after treatment  SCr after treatment and 6 months later
MEPEX 2007	Immunosuppression as for the control group PE: 7 x 60 mL/kg in first 2 weeks after diagnosis	Immunosuppression IV MP: 3 pulses of 1000 mg followed by oral CPA and a tapering regimen of prednisolone	Death at 3 and 12 months  Dialysis at 3 and 12 months  Side effects  SCr at 12 months
PEXIVAS 2013	Treatment group 1 (a, b)  Adjunctive PE: 7 exchanges over 14 days 60 mL/kg Treatment group 2 (a, b)  No plasma exchange	Treatment group 1a, 2a  Reduced dose prednisolone Treatment group 1b, 2b  Full dose prednisolone	Time to the composite of death from any cause and ESKD Death Dialysis Quality of life Serious infections Serious adverse events Sustained remission
Pusey 1991	Induction/maintenance therapy as for control group PE: 5 x 4 L exchanges of 5% albumin (plasma protein fraction) within first week. Two units of fresh frozen plasma were given at end of exchange. Total number of exchanges determined by clinical response	Induction therapy, 8 weeks of: 60 mg/day prednisolone, reducing by 15 mg at weekly intervals to 30 mg/day, then 5 mg at weekly intervals to 20 mg/day and then more slowly as clinically indicated CPA: 3 mg/kg/day or 2 mg/kg/day for those over 55 years AZA: 1 mg/kg/day or no AZA for those over 55 years Maintenance therapy CPA stopped after 8 weeks in those with remission and AZA increased to 2‐3 mg/kg/day, together with tapering doses of prednisolone	Improvement (fall in SCr > 25% or rise in CrCl > 25%; recovery of kidney function in those initially on dialysis)  SCr  Dialysis  Death  Adverse events
Rifle 1980	Immunosuppression as per control group PE: 5 sessions during 5 successive days, then 3 sessions/week until 15 days after SCr reached a plateau Treatment could not exceed 2 months 150% plasma volume was exchanged for albumin and saline solution at each session	Immunosuppression IV pulse MP: 15 mg/kg/day for 3 days, tapered to 15 mg/day for 3 days, then 3 new pulses, then 15 mg/day for 7 weeks CPA: 2 to 3 mg/kg/day for 2 months Calcium heparinate 9 days after kidney biopsy for the duration of the study	Dialysis: 2, 6 12, 24 months  CrCl: 2, 6 and 12 months.  Recovery (off dialysis) according to initial SCr level  Recovery (off dialysis) according to initial % of crescents  Death  Circulating immune complexes  Pathology changes  Adverse events (septicaemia)
Szpirt 2011	Immunosuppression as for control group PE: 6 sessions of 4L PE with 3% albumin in Ringer's lactate solution replacement on alternate days. Performed using Gambro F‐1000 filters. If c‐ANCA titres > 320 or PR3‐ANCA > 25 U/mL on ELISA after 6 sessions the additional 3 to 6 sessions performed	Immunosuppression Prednisolone: 80 mg/day for 3 weeks tapered to 5 mg then stopped after 9 months CPA: 1.5 mg/kg/day for 3 months	Kidney outcomes: progression, remission and dialysis at 1, 3 and 12 months Progression defined as unchanged Cr if initial Cr > 300 µM or 15% increase if initial Cr < 300 µM. Remission defined as 15% fall in Cr from inclusion Relapse: clinical symptoms of active disease and at least 2 of: a 2‐fold increase in ANCA titre, 20% increase in Cr, increase in proteinuria and increase in ESR or CRP Kidney and patient survival to 5 years
Zauner 2002	Immunosuppression as for control group PE: 40 mL/kg with FFP replacement daily for 3 exchanges, continued if no response to a maximum of 12 exchanges; mean number of PE = 6	Immunosuppression IV MP: 500 mg/day for 3 days. Prednisolone 80, 60 then 40 mg/day for a week each. Dose tapered by 5 mg/day each week to maintenance dose of 10 mg/day CPA: 2 mg/kg/day oral from day 1; dose reduced for side effects. Continued for 6 months after remission	Death ESKD SCr Adverse events

Study ID	Treatment	Control	Study outcomes
Adu 1997	PCYP Intermittent pulses of CPA and CPA and prednisolone were given IV at 0, 2 and 4 weeks The same dose was then given as oral pulses over a 3‐day period. The interval between pulses was gradually increased.	CCAZP Continuous CPA, prednisolone and AZA Initial treatment: 0.85 mg/kg prednisolone then tapering according to a predefined schedule for 72 weeks CPA given until a clinical decision that remission had been achieved at which point CPA was stopped and AZA commenced at 1.5 mg/kg/day	Complete and partial remission  Relapse  Adverse events  Treatment failure  Chronic dialysis
CYCLOPS 2004	Immunosuppression as for control group Pulse CPA 3 IV pulses of CPA (15 mg/kg) 2 weeks apart followed by 3 weekly pulses (15 mg/kg (IV) or 5 mg/kg orally for 3 days) until remission then for another 3 months. Max dose 1.2 g. Reductions for age > 60 years and SCr > 300 µM and for previous low leukocyte nadir	Immunosuppression AZA: 2 mg/kg/day orally after induction therapy until month 18 Prednisolone: 1 mg/kg orally tapered to 12.5 mg/day at the end of month 3 and 5 mg at end of study Continuous CPA Oral CPA: 2 mg/kg/day to remission then 1.5 mg/kg for further 3 months. Max oral dose 200 mg Reductions for age > 60 years and leukopenia	Time to remission  Proportion of patients who achieved remission at 6 and 9 months  Proportion with major and minor relapses  Death  Change in kidney function  Adverse events  Cumulative dose of CPA and prednisolone. calculated at 3, 6, 9, 12, 15 and 18 months
Guillevin 1997	Initial regimen as for control group IV pulse CPA Mean dose 0.7 g/m² adjusted for neutrophil count and kidney function, administered every 3 weeks until complete remission and 1 year thereafter. Then every 4 weeks for 4 months, every 5 weeks for 4 months and every 6 weeks until discontinuation after 2 years if treatment. Adjusted up or down based on neutrophil count	Initial regimen IV MP: 15 mg/kg/day for 3 days then oral prednisolone 1 mg/kg/day. One pulse of IV CPA was administered (0.7 g/m²) the day after the last IV MP and concurrently with the 1st day of oral prednisolone. Oral prednisolone (1 mg/kg/day) for 6 weeks. If complete remission was achieved daily dose was tapered by 2.5 mg every 10 days until a level equivalent to half the original dose was reached. This was maintained for 3 weeks and then further decreased by 2.5 mg every 10 days to 20 mg/day. More gradual tapering for doses < 20 mg/day with decrease of 1mg/day every 2 weeks to 10 mg/day and then 1mg/month until discontinuation Oral CPA 2 mg/kg/day on day 10 after initial CPA pulse, after neutrophil nadir had been reached. 1 year after complete remission, oral CPA was tapered by 25% every 4 months until discontinuation. Dose adjusted up or down based on neutrophil count	Treatment failure  Complete remission  Partial remission  Relapse  Death  Side effects
Haubitz 1998	Steroid regime as for control group IV pulse CPA 0.75 g/m² every 4th week. If CrCl < 30 mL/min, initial dosage was 0.5 g/m² and increased to 0.75 g/m² provided leucocyte counts remained > 3000/mL CPA dose adjusted to the peripheral leucocyte count and dose reduced in increments of 0.125 g/m². If leucocyte count < 2500/mL dose was reduced by 0.25 g/m² Antiemetic drugs were given immediately before and 8 h after treatment. At least 3 L of fluid was administered on day of CPA treatment	Steroid regime Days 1 to 3, 0.5 g IV MP. Day 4 to 14 1 mg/kg/day oral prednisolone. Day 15 onwards tapering of steroids with a reduction of 10 mg/week. When a dosage or 30 mg/day was reached, tapering changed to 5 mg/week, at 15 mg/day tapering changed to 2.5 mg/week. This tapering protocol was not mandatory, however dosage had to be ≤ 12.5 mg/day at 6 months Oral daily CPA 2 mg/kg/day. If CrCl < 30 mL/min, initial dosage started at 1.5 mg/kg/day and increase to 2 mg/kg/day after 2 weeks provided leucocyte counts were > 3000/mL CPA dose reduced in step < 1500/mL drug was withheld until increased to 2500/mL	Complete remission  Partial remission  Relapse  Serious infection  ESR, CRP, ANCA, Hb, WBC platelet count, SCr, urea, CrCl, quantitative proteinuria, urinary microscopy, alanine aminotransferase, aspartate aminotransferase, gonadal toxicity (FSH)

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Three months	2	169	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.49, 2.15]
1.2 Six months	2	63	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.08, 6.13]
1.3 One year	5	267	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.57, 1.92]
1.4 Two years	4	120	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.49, 3.38]
1.5 Five years	3	80	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.71, 2.04]
1.6 Death at any time point	6	957	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.72, 1.29]
2 Kidney function: serum creatinine	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 One month	3	73	Mean Difference (IV, Random, 95% CI)	‐111.37 [‐318.19, 95.45]
2.2 Two months	1	23	Mean Difference (IV, Random, 95% CI)	‐79.70 [‐198.76, 39.36]
2.3 Three months	2	50	Mean Difference (IV, Random, 95% CI)	36.62 [‐23.32, 96.57]
2.4 Six months	2	49	Mean Difference (IV, Random, 95% CI)	9.82 [‐180.10, 199.74]
2.5 Twelve months	4	156	Mean Difference (IV, Random, 95% CI)	23.52 [‐17.19, 64.22]
3 Dialysis	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 One month	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.01, 1.52]
3.2 Three months	2	147	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.23, 0.78]
3.3 Six months	4	104	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.13, 1.10]
3.4 Twelve months	6	235	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.29, 0.72]
3.5 Five years	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.64]
3.6 At any time point	1	704	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.70, 1.27]
4 Sustained remission	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5 Adverse events	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 Serious infections	5	956	Risk Ratio (M‐H, Random, 95% CI)	1.26 [1.03, 1.54]
5.2 Myocardial infarction	1	52	Risk Ratio (M‐H, Random, 95% CI)	2.78 [0.31, 24.99]
5.3 Lung haemorrhage	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.11, 3.39]
5.4 Subarachnoid haemorrhage	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.01, 7.26]
5.5 Gastrointestinal haemorrhage	2	63	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.08, 4.69]
5.6 Anaphylaxis	1	31	Risk Ratio (M‐H, Random, 95% CI)	2.82 [0.12, 64.39]
5.7 Serious adverse events	1	704	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.89, 1.11]
5.8 Total number of adverse events	5	956	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.91, 1.12]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	2	162	Risk Difference (M‐H, Random, 95% CI)	0.06 [‐0.01, 0.13]
2 Dialysis	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Relapse	2	162	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.64]
4 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1 Serious infections	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Leukopenia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Total side effects (episodes/patient‐months)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Relapse	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 All relapses	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Major relapse	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Severe adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Infections	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Leukopenia	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Methods	Study design: parallel RCT Study duration: not reported Duration of follow‐up (months): treatment group (0.7 to 63.6); control group (2.5 to 54.8)
Participants	Country: UK Setting: single centre Inclusion criteria: 15 to 70 years with new‐onset systemic necrotizing vasculitis. WG, classical PAN and MPA diagnosed by histological or radiological evidence Number: treatment group (24); control group (30) Median age, range (years): treatment group (47, 22 to 70); control group (62, 15 to 70) Sex (M/F): treatment group (17/7); control group (18/12) Exclusion criteria: not reported
Interventions	Treatment group PCYP Intermittent pulses of CPA and MP CPA and MP were given IV at 0, 2 and 4 weeks The same dose was then given as oral pulses over a 3‐day period. The interval between pulses was gradually increased Control group CCAZP Continuous CPA, MP and AZA Initial treatment: 0.85 mg/kg prednisolone then tapering according to a predefined schedule for 72 weeks CPA given until a clinical decision that remission had been achieved at which point CPA was stopped and AZA commenced at 1.5 mg/kg/day Other treatment Escalation of immunosuppression was allowed for severe or life‐threatening disease. This included PE and IVIg Duration of treatment: 72 weeks
Outcomes	Complete and partial remission Absence of clinical symptoms of vasculitis, resolution of pulmonary, renal or other organ changes or stable changes consistent with scarring and stabilization Complete remission was defined as the absence of any active disease for at least one month Relapse Re‐emergence of new clinical symptoms attributable to vasculitis or worsening of original manifestations after 4 weeks of complete clinical remission had been achieved infection not included) Adverse events Leukopenia, infective episodes, thrombocytopenia, steroid‐induced diabetes, osteoporosis, basal‐cell carcinoma, septicaemia, pancreatitis, bronchial neoplasm Treatment failure Disease activity > 50% Chronic dialysis
Notes	Follow‐up PCYP: median 35.1 months (range 0.7 to 63.3) CCAZP: median 42.5 months (range 2.5 to 64.8) CCAZP: median duration of CPA was 3 months (range 1.5 to 10) Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random numbers, stratified for kidney function (< 250, 251 to 500, > 500 mmol/L)
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Study could not be blinded to investigators or participants; unlikely to affect results
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	All outcomes clearly stated
Other bias	High risk	Patients in PCYP had worse kidney function than the CCAZP group (median SCr 234, range 60 to1082 mmol/L vs 139, range 72 to 1255 mmol/L (P = 0.3))

Methods	Study design: parallel, open‐label study Study duration: June 2005 to March 2008 Duration of follow‐up: 36 months
Participants	Countries: Belgium, France Setting: multicentre (65 sites) Inclusion criteria: newly diagnosed PAN not related to hepatitis B virus infection, EGPA, GPA, or MPA; 2) to satisfy the 1990 American College of Rheumatology criteria and/or 1994 Chapel Hill nomenclature definitions (10 to 13); 3) to be in or after the year of their 65th birthday at the time of SNV diagnosis; and 4) to provide written informed consent. Patients could have started corticosteroids, but for no more than 1 month prior to enrolment, and could not have started CYC and/or received any other immunosuppressant before inclusion Number: treatment group (53); control group (51) Mean age ± SD (years): treatment group (75.1 ± 6.2); control group (75.3 ± 6.4) Sex (M/F): treatment group (27/26); control group (32/19) Exclusion criteria: not reported
Interventions	Treatment group Corticosteroids: started at 1 mg/kg then progressively tapered after 3 weeks and stopped at 9 months CPA pulses: 500 mg every 2 weeks for first 3 pulses then every 3 weeks until remission Patients switched to MTX or AZA (or MMF for those with intolerance to MTX or AZA) Control group Corticosteroids: started at 1 mg/kg the progressive tapered after 3 weeks until stopped at 26 months CPA pulses: 500 mg/m² for 6 doses with a further 3 doses for consolidation prior to maintenance therapy
Outcomes	Occurrence of 1 or more serious adverse events defined as potentially life‐threatening adverse events, requiring hospitalisation or its prolongation, causing significant disability, or resulting in death. Death Remission Relapse Serious adverse event‐free survival Progression free survival
Notes	Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed centrally. The randomisation list was computer generated, using random blocks of 6, with a between‐arm randomisation ratio of 1:1
Allocation concealment (selection bias)	Unclear risk	Sealed opaque envelopes
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Unclear risk	All outcomes reported
Other bias	Unclear risk	Study appears free of other biases

Methods	Study design: parallel RCT Duration of study: not reported Duration of follow‐up: 18 months
Participants	Countries: 11 European countries Setting: multicentre (39 sites) Inclusion criteria: diagnosis of WG, MPA or kidney limited vasculitis. Renal involvement, other threatened loss of function of vital organ, or both. ANCA positivity. ANCA negative patients enrolled with biopsy evidence of vasculitis Number: treatment group (79); control group (76) Mean age, range (years): treatment group (59, 20 to 77); control group (57, 20 to 76) Sex (M/F): treatment group (33/46); control group (40/36) Exclusion criteria: cytotoxic drug in previous year; other multisystem autoimmune disease; hepatitis B e antigenaemia; hepatitis C; HIV infection; SCr > 500 μmol/L; cancer; pregnancy; aged < 18 years or >75 years
Interventions	Treatment group CPA: 1.5 mg/kg/day from remission Switched to AZA (2 mg/kg/day) 12 months after study entry Control group After remission induction AZA: 2 mg/kg/day Prednisolone: 10 mg/day Co‐interventions (both groups) Remission induction with oral CPA (2 mg/kg/day) and prednisolone (1 mg/kg/day) tapered to 0.25 mg/kg/day by 12 weeks From 12 months both groups received AZA (1.5 mg/kg/day) and prednisolone (7.5 mg/day)
Outcomes	Relapse by 18 months Side effects including leukopenia and infections.
Notes	Stopping point: 18 months after study entry Funding source: reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed centrally with the use of permuted blocks of four within each country, with stratification according to diagnosis."
Allocation concealment (selection bias)	Low risk	Not reported, however assumed to be performed centrally
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	Supported by contracts (BMH1‐CT93‐1078, CIPD‐CT94‐0307, BMH4‐CT97‐2328, and IC20‐CT97‐0019) with the European Union

Methods	Study design: open‐label, parallel RCT Duration of study: not reported Duration of follow‐up: 18 months
Participants	Country: 14 countries (Europe, Mexico) Setting: multicentre (42 sites) Inclusion criteria: newly diagnosed WG, MPA, or renal‐limited MPA, renal involvement: at least one of: SCr > 150 µmol/L and < 500 µmol/L, biopsy evidence of necrotizing GN, erythrocyte casts, or haematuria and proteinuria, confirmatory histology or ANCA positivity Number: treatment group 1 (76); treatment group 2 (73) Mean age ± SD (years): treatment group 1 (56.6 ± 15.3); control group 2 (58.2 ± 13.7) Sex (M/F): treatment group 1 (41/35); treatment group 2 (47/26) Exclusion criteria: other multisystem autoimmune disease; hepatitis B or C virus or HIV infection/ SCr > 500 µmol/L; previous cancer; pregnancy; < 18 years or > 80 years
Interventions	Treatment group 1 Pulse CPA 3 IV pulses of CPA (15 mg/kg) 2 weeks apart followed by 3 weekly pulses (15 mg/kg (IV) or 5 mg/kg orally for 3 days) until remission then for another 3 months. Max dose 1.2 g. Reductions for age > 60 years and SCr > 300 µM and for previous low leukocyte nadir Treatment group 2 Continuous CPA Oral CPA: 2 mg/kg/day to remission then 1.5 mg/kg for further 3 months. Max oral dose 200 mg Reductions for age > 60 years and leukopenia Co‐interventions (both groups) AZA: 2 mg/kg/day orally after induction therapy until month 18 Prednisolone: 1 mg/kg orally tapered to 12.5 mg/day at the end of month 3 and 5 mg at end of study
Outcomes	Primary outcome: time to remission defined as absence of new or worse signs of disease activity on the BVAS Proportion of patients who achieved remission at 6 and 9 months Proportion with major and minor relapses Death Change in kidney function Adverse events Cumulative dose of CPA and prednisolone calculated at 3, 6, 9, 12, 15 and 18 months
Notes	Funding source: reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Random assignments were computer‐generated and performed centrally by permuted blocks of 4, stratified by country and disease." randomised 1:1 to treatments.
Allocation concealment (selection bias)	Low risk	Quote: "Patients were enrolled by their treating physician and registered with the central trial coordinating office by fax submission of a form that contained information on centre, date of birth, sex, disease, and creatinine level."
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Open‐label study, unable to blind interventions; unlikely to affect outcomes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Eleven patients were withdrawn before random assignment: 1 declined further participation, 8 were withdrawn by their physician, and 2 did not meet the entry criteria
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	Quote: "This trial was funded by the European Union (European Community Systemic Vasculitis Trial project, contract BMH1‐CT93‐1078 and CIPD‐CT94‐0307, and Associated Vasculitis European Randomised Trial project, contract BMH4‐CT97‐2328 and IC20‐CT97‐0019)."

Methods	Study design: open‐label RCT Duration of study: January 2006 to December 2008 Duration of follow‐up: 6 months
Participants	Country: China Setting: single centre Inclusion criteria: MPA with moderate to severe renal involvement (MPA by Chapel Hill Nomenclature) Number: treatment group 1 (19); treatment group 2 (22) Mean age ± SD (years): treatment group 1 (55.1 ± 11.5); treatment group 2 (57.3 ± 12.7) Sex (M/F): treatment group 1 (7/12); treatment group 2 (9/13) Exclusion criteria: severe lung haemorrhage (haemoptysis > 300 mL/24 h or hypoxaemia); CNS involvement; other life‐threatening situations; cytotoxic drug in the previous 6 months; severe infection in the last month; active hepatitis or abnormal liver function; pregnancy; malignancies; > 70 years
Interventions	Treatment group 1 MMF (oral): 1.0 g/day (1.5 g/day if weight > 70 kg) Treatment group 2 CPA (IV): 1.0 g/pulse (0.8G if body weight < 50 kg) monthly No switch to maintenance treatment indicated Co‐interventions (both groups) MP (IV): 360 to 500 mg/day for 3 days, then oral prednisone 0.6 to 0.8 mg/kg/day, gradually tapered
Outcomes	Primary outcome Remission at 6 months: remission defined as BVAS of 0 under low dose of prednisolone (< 7.5 mg) Secondary outcomes Kidney function at 6 months Adverse events Maintenance dialysis defined as HD or PD for at least 6 weeks without subsequent kidney recovery signs
Notes	Treatment reduced for pulmonary infection with hypoxaemia, WCC < 3 x 10⁹/L or severe GI symptoms No plasmapheresis or immunoadsorption TMP/SMX recommended but not mandated Funding source: reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients entered into the study were divided into two groups randomly according to the randomised number table"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Unable to blind participants and personnel; unlikely to affect outcomes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	5 patients lost to follow‐up and presumed failed treatment, 3 in CPA and 2 in MMF groups
Selective reporting (reporting bias)	Low risk	All study and review outcomes were reported
Other bias	Low risk	Study was supported by grants from the National Natural Science Foundation of PR China (30801148) to Fei Han and the Key Projects in the National Science & Technology Pillar Program in the Eleventh Five‐Year Plan Period (2008BAI60B04) to Jianghua Chen

Methods	Study design: parallel, open‐label RCT Duration of study: April 2002 to May 2004 Duration of follow‐up: 4 years
Participants	Countries: 11 Setting: multicentre (42) Inclusion criteria: newly diagnosed patients with WG, MPA or RLV; ANCA positivity. ANCA positivity requires PR3‐ANCA or a typical c‐ANCA pattern by IIF, preferably confirmed by anti‐PR3 ELISA; MPO‐ANCA determined by ELISA requires demonstration of p‐ANCA, and p‐ANCA by IIF requires confirmation by anti‐MPO ELISA; optionally, central review of ANCA serology can be performed; 18 to 75 years Number: treatment group 1 (76): treatment group 2 (80) Mean age ± SD (years): treatment group 1 (54.2 ± 12.8): treatment group 2 (55.1 ± 15.2) Sex (M/F): treatment group 1 (46/30): treatment group 2 (58/22) Exclusion criteria: any cytotoxic drug within previous year, unless started within one months of entry and according to the protocol design; co‐existence of another systemic autoimmune disease (e.g. SLE, Hepatitis B or HCV, HIV positivity); failure to achieve remission after 6 months of CPA therapy; failure to control progressive disease with induction protocol; malignancy (usually exclude unless agreed with trial coordinator); pregnancy or inadequate contraception; < 18 years and > 75 years; ESKD unless active extrarenal disease requires treatment (temporal dependency of HD is not an exclusion criterion); inability for informed consent
Interventions	Treatment group 1 MMF: 2 g/day; reduced to 1500 mg/day after 12 months, 1000 mg/day after 18 months, and withdrawn after 42 months Complete blood cell count was taken weekly for the first month, biweekly for the second month, and then monthly for the first year, and then every 3 months MMF use was stopped for presence of leukopenia until recovery and reintroduced with the dose reduced by 500 mg/day. Patients intolerant of the initial dose were reduced to 1000 mg/day and increased monthly by 500 mg/day increments to the 2000 mg/day target or the highest tolerated dose. Dose reduction to 1000 mg/day was recommended for a GFR < 25 mL/min/kg Treatment group 2 AZA: 2 mg/kg/day (max 200 mg), rounded down to the nearest 25 mg increment. The dose was reduced to 1.5 mg/kg/day after 12 months, 1 mg/kg/day after 18 months, and withdrawn after 42 months Complete blood cell count and transaminases were measured weekly for 1month, bimonthly for the first year, and then every 3months AZA use was stopped for presence of leukopenia (4106/L) until recovery, and then reintroduced with the dose reduced by 25 mg/day. Patients with leukopenia were monitored weekly for a minimum of 4 weeks Initial treatment (both groups) 1 mg/kg/day (maximum 80 mg) of oral prednisolone, which was reduced to 0.75 mg/kg/day after 1 week, 0.50 mg/kg/day after 2 weeks, 0.40 mg/kg/day after 4 weeks, 0.30 mg/kg/day after 7 weeks, 0.28 mg/kg/day after 10 weeks, and 0.25 mg/kg/day after 13 weeks; prednisolone was reduced to 15 mg/day at the start of the remission regimen, tapered to 5 mg/day after 12 months, and was withdrawn after 24 months
Outcomes	Primary outcome measure Time to first relapse Secondary outcome measures Relapse rate Rate of side‐effects and intolerance Proteinuria Cumulative doses (AZA, steroids, MMF) AUC for BVAS SF‐36 or VDI Evolution of titres of ANCA and CRP
Notes	Funding source: This trial received funding from the Cambridge Biomedical Research Centre, the Programme Hospitalier de Recherche Clinique Regionale 2001, and the French Ministry of Health. Hoffman‐La Roche Ltd provided reimbursement for the study drugs to investigators in Germany, France, and Switzerland; for patients recruited in Belgium, France, and Switzerland; and for trial insurance in Germany. Dr Hiemstra is supported by the Cambridge Biomedical Research Centre. Dr Walsh is supported by a randomised Controlled Trial Mentoring Award from the Canadian Institute for Health Research, a Clinical Scholar award from the Alberta Heritage Foundation for Medical Research, and a Krescent Postdoctoral Training Award
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "1:1 ratio with the use of a minimized central computerized randomisation procedure. Randomization was stratified for age, diagnosis (Wegener granulomatosis vs MPA), and route of cyclophosphamide administration (daily oral vs intravenous pulse)."
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Unable to blind participants and personnel; unlikely to affect outcomes
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	Reported planned outcomes
Other bias	Low risk	Funding source stated and had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript

PERMALINK

Interventions for renal vasculitis in adults

Giles D Walters

Narelle S Willis

Tess E Cooper

Jonathan C Craig

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Types of treatments for remission induction

Types of maintenance therapies

Diagnoses

Excluded studies

Risk of bias in included studies

2.

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Detection bias

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Plasma exchange as adjunctive therapy for renal vasculitis.

Summary of findings 2. Pulse cyclophosphamide versus continuous cyclophosphamide for remission induction.

Summary of findings 3. Rituximab versus cyclophosphamide for renal vasculitis for remission induction.

Summary of findings 4. Mycophenolate mofetil versus cyclophosphamide for remission induction.

Summary of findings 5. Intravenous immunoglobulin versus placebo for renal vasculitis in adults.

Summary of findings 6. Azathioprine versus cyclophosphamide for maintenance therapy.

Summary of findings 7. Azathioprine versus methotrexate for maintenance therapy.

Summary of findings 8. Antibiotics versus placebo for maintenance therapy.

Summary of findings 9. Leflunomide versus methotrexate for maintenance therapy.

Remission induction studies

1: Plasma exchange as adjunctive therapy

1.3. Analysis.

1.5. Analysis.

Methods	Study design: parallel, open‐label, pragmatic, multicentre, RCT Duration of study: enrolment November 2012 to November 2013 Duration of follow‐up: 28 months
Participants	Country: France Setting: multicentre (59 sites) Inclusion criteria: > 18 years; had newly diagnosed or relapsing GPA or MPA (defined by the Chapel Hill Consensus nomenclature); in complete remission after induction therapy, combining glucocorticoids and cyclophosphamide, RTX or methotrexate (as decided by each investigator), in accordance with French and international recommendations; BVAS of 0 (score range: 0–63, with higher scores indicating more active disease) defined complete remission. Number: treatment group 1 (81); treatment group 2 (81) Mean age ± SD (years): treatment group 1 (62 ± 14); treatment group (59 ± 13) Sex (M/F): treatment group 1 (31/50); treatment group (37/44) Exclusion criteria: another systemic vasculitis; induction with an agent not recommended; active disease; incapacity for informed consent; non‐compliance; allergy to the study medication; pregnancy; breastfeeding; HIV, hepatitis B or C; severe infection declared during the 3 months before randomisation; cancer or malignant blood disease diagnosed during the 5 years preceding vasculitis diagnosis; participation in another clinical research protocol during the 4 weeks before inclusion; any clinical or psychiatric disorder that could expose the patient to a greater risk of an adverse event or could prevent treatment administration and patient follow‐up according to the protocol; severe immunosuppression; administration of live vaccine during the 4 weeks before inclusion; severe chronic obstructive pulmonary diseases (maximum expiratory volume < 50% or dyspnoea grade III); chronic heart failure (dyspnoea NYHA III or IV); history of recent acute coronary syndrome unrelated to vasculitis; patients not enrolled in the French national health insurance
Interventions	Treatment group 1 Tailored schedule: fixed 500 mg RTX infusions on day‐0 post‐randomisation, then every 3 months until month 18, when CD19 lymphocytes exceeded 0/mm³ or ANCA status (reappearance)/titre (higher) differed from the previous determination Treatment group 2 Fixed schedule: 500 mg of RTX on days 0 and 14 post‐randomisation, then 6, 12 and 18 months after the first infusion
Outcomes	Major relapse Death Severe adverse events Serious infections
Notes	Quote: "2 new relapses occurred after the followup (month 28) and were censured from the main analysis".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomised at a 1:1 ratio". "An independent statistician provided the computer‐generated randomisation sequence, stratified by newly diagnosed or relapsing AAV"
Allocation concealment (selection bias)	Low risk	Quote: "An independent statistician provided the computer‐generated randomisation sequence, stratified by newly diagnosed or relapsing AAV. Randomisation was centralised through electronic case‐report forms (eCRF) to assure allocation concealment"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study, no blinding of participants or clinicians
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Outcome assessors not blinded, open‐label trial
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for and all outcome data complete
Selective reporting (reporting bias)	Low risk	Stated outcomes reported
Other bias	High risk	Pharmaceutical funding of study drug

Methods	Study design: open label parallel RCT Duration of study: December 1997 to June 2011 Duration of follow‐up: 24 months
Participants	Country: Italy Setting: single centre Inclusion criteria: diagnosis of clinically active systemic necrotizing vasculitis; aged 18 to 80 years; life‐expectancy > 1 year; written informed consent; randomisation performed only if GFR > 30 Number: treatment group 1 (38); treatment group 2 (33) Median age, IQR (years): treatment group 1 (52, 18 to 77); treatment group 2 (56, 36 to 71) Sex (M/F): treatment group 1 (19/19); treatment group 2 (17/16) Exclusion criteria: CrCl < 10 mL/min/1.73 m²; aminotransferase levels more than twice the upper limit of the normal range; HBsAg positivity; anti‐HCV Ig and HCV‐RNA positivity; HIV positivity; active malignancies; coexistence of connective tissue disease; prednisolone, CPA or MTX hypersensitivity; pregnancy
Interventions	Treatment group 1 MTX: 15 mg/week increased to 0.3 mg/kg/week Patients with eGFR of 30 to 50 mL/min/1.73 m² received 75% of the full CPA dose and half of the full MTX dose Treatment group 2 CPA: 1.5 mg/kg/day orally; treatment continued for 12 months Co‐interventions Both groups received induction therapy with 3 IV pulses of 500 mg MP followed by oral prednisone and CPA. Oral prednisolone starting at 1mg/kg/day, gradually tapered to 5 mg at month 6 and oral CP dose was 2mg/kg/day
Outcomes	Relapse at 12 months, 18 and 24 months Major and minor relapses Change in eGFR Death Adverse events
Notes	Funding source: "The author(s) received no specific funding for this work"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer algorithm
Allocation concealment (selection bias)	High risk	Not performed
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Unclear risk	All outcomes reported
Other bias	Low risk	Study appears free of other biases

Methods	Study design: parallel, open‐label, 2 x 2 factorial RCT Duration of study: not reported Duration of follow‐up: not reported
Participants	Countries: USA, Australia, Europe Setting: multicentre (67 sites) New or previous clinical diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis consistent with the Chapel‐Hill consensus definitions AND positive test for proteinase 3‐ANCA or myeloperoxidase‐ANCA AND severe vasculitis defined by at least one of the following: Renal involvement with both: renal biopsy demonstrating focal necrotizing glomerulonephritis or active urine sediment characterized by glomerular haematuria or red cell casts and proteinuria AND eGFR < 50 mL/min/1.73 m² Pulmonary haemorrhage due to active vasculitis defined by a compatible chest X‐ray or CT scan (diffuse pulmonary infiltrates) AND the absence of an alternative explanation for all pulmonary infiltrates (e.g. volume overload or pulmonary infection) AND At least one of the following: evidence of alveolar haemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage; observed haemoptysis; unexplained anaemia (< 10 g/dL) or documented drop in Hb >1 g/dL); increased diffusing capacity of carbon dioxide Number: treatment group 1 (352); treatment group 2 (352) Mean age ± SD (years): treatment group 1 (62.8 ± 14.4); treatment group 2 (63.5 ± 13.7) Sex (M/F): treatment group 1 (203/149); treatment group 2 (194/158) Exclusion criteria: diagnosis of vasculitis other than granulomatosis with polyangiitis or microscopic polyangiitis; positive anti‐glomerular basement membrane antibody test or renal biopsy demonstrating linear glomerular immunoglobulin deposition; receipt of dialysis for > 21 days immediately prior to randomisation or prior renal transplant; aged < 15 years; pregnancy; inability or unwillingness to comply with birth control/abstinence; treatment with > 1 IV dose of CPA and/or > 14 days of oral CPA and/or > 14 days of prednisone/prednisolone (> 30 mg/day) and/or >1 dose of RTX within the 28 days immediately prior to randomisation; a comorbidity that, in the opinion of the investigator, precludes the use of CPA, glucocorticoids, or PE or absolutely mandates the use of PE
Interventions	Treatment group 1 (a, b) Adjunctive PE: 7 exchanges over 14 days 60 mL/kg Treatment group 2 (a, b) No plasma exchange Treatment group 1a, 2a Reduced dose prednisolone Treatment group 1b, 2b Full dose prednisolone
Outcomes	Time to the composite of death from any cause and ESKD Death Dialysis Quality of life Serious infections Serious adverse events Sustained remission
Notes	Funding source: Centre. CDP is supported by the Imperial Biomedical Research Centre. PEXIVAS is funded by the National Institutes of Health Research (UK), the Food and Drug Administration Office of Orphan Drugs Program (USA) (R01FD003516), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (USA) (U54AR057319), the Office of Rare Diseases Research (USA), the Canadian Institute of Health Research (Canada), the National Health and Medical Research Council (Australia), and Assistance Publique (France). The trial has received in‐kind plasma exchange disposables from TerumoBCT, Fresenius Australia, and Gambro Australia.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central web‐based sequence generation with minimisation stratified by severity of renal disease, age, ANCA subtype, severity of pulmonary haemorrhage and induction therapy
Allocation concealment (selection bias)	Low risk	Central web‐based system
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Unclear risk	Study appears free of other biases

Study	Reason for exclusion
Basu 2017	Not induction or maintenance therapy, treating fatigue
CHUSPAN 2 2017	Mixed population: EGPA, MPA or PAN
De Vita 2012	Wrong population: patients with cryoglobulinaemic vasculitis
Harper 2018	Not induction or maintenance therapy, treating fatigue
Imai 2006	Wrong patient population, mostly IgA; there were 5 patients with likely ANCA vasculitis in one group
Ribi 2010	Excluded patients with kidney disease (raised Cr and proteinuria) and they were only randomised after a period of steroid treatment. It is a study of treatment failure and relapse treatment rather than induction or maintenance therapy
Rifle 1990	Wrong diagnosis for most patients. Immunoglobulin deposits demonstrated in renal biopsies

Methods	Parallel RCT
Participants	19 patients with newly diagnosed ANCA‐associated small vessel vasculitis
Interventions	MMF versus CPA for 6 months
Outcomes	BVAS, renal insufficiency, anaemia, pulmonary infection, severe infection
Notes	Abstract‐only publication; data cannot be extracted/meta‐analysed

Methods	Pilot parallel RCT
Participants	Patients with AAC
Interventions	Treatment group 1: CTLA4‐Ig (n=6) Treatment group 2: placebo (n=1) Additional therapies: all patients subsequently receiving a standard reducing regime of MTX and prednisolone
Outcomes	Disease activity monitored ANCA titres Inflammatory markers Hepatic and renal function SF36 indices Adverse events
Notes	Abstract‐only publication; data cannot be extracted/meta‐analysed

Methods	Parallel, open‐label RCT
Participants	ANCA vasculitis as defined by a positive MPO‐ and/or PR3‐ANCA test together with clinical features characteristic of ANCA‐positive diseases as detailed in the 2012 Chapel Hill Consensus Conference Definitions eGFR > 30 mL/min/1.73 m²; 18 to 82 years; treated with RTX‐induced continuous B cell depletion and in remission (defined by a modified BVAS‐WG=0 AND a prednisone dose ≤ 7.5 mg) for at least 24 months. CD20 (B cells) undetectable at time of enrolment/randomisation; urine HCG negative for women of child bearing potential and not planning to become pregnant for at least 12 months from enrolment and at least 12 months after any study related RTX dose; judged to be otherwise healthy by the Investigator, based on medical history and physical examination (no known active disease process for which life expectancy is less than 36 months) Exclusion criteria: secondary disease: disease suspected to be induced by levamisole‐adulterated cocaine; all transplanted patients Treatment: additional immunosuppressive agents other than RTX and/or total daily prednisone dose > 7.5 mg; hypogammaglobulinaemia: IgG level < 250 mg/dL; terminal cancer or other primary illness with life expectancy < 36 months; active anti‐GBM disease and other known autoimmune disease for which the need for additional immunosuppression is likely; pregnancy or breastfeeding
Interventions	Treatment group 1 IV RTX: 1g 2 to 3 weeks apart when B cells rise ≥10 cells/mm³ Treatment group 2 IV RTX: 1 g 2 to 3 weeks apart when ANCA level rises above predetermined value (MPO 5‐fold from baseline, 4 ‐old above normal range, PR3 4‐fold from baseline, 2‐fold from normal range)
Outcomes	Number of disease relapses as defined by a (BVAS/WG) ≥ 2 (3 years) Number of serious adverse events (3 years) Composite of disease relapse (defined a BVAS/WG ≥ 2) and serious adverse events (3 years) Hypogammaglobulinaemia defined as an IgG < 400 mg/dL (3 years) Patient Survival (3 years) Health‐related quality of life as assessed by the Short Form Health Survey (SF‐36) score (3 years) RTX utilization measured in grams/patient (3 years) Organ damage as assessed by the Vasculitis Damage Index (VDI) (3 years) Number of major relapses defined as a BVAS/WG ≥ 3 (3 years) Number of infections defined as receiving oral or IV antibiotics (3 years)
Notes	Abstract‐only publication; data cannot be extracted/meta‐analysed

Trial name or title	A randomised phase 3 trial evaluating the safety and efficacy of avacopan in patients with new or relapsing ANCA‐associated vasculitis
Methods	Study design: parallel, double‐blind RCT Study duration: 60 weeks Duration of follow‐up: unclear
Participants	Inclusion criteria Clinical diagnosis of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis Male and female subjects, aged at least 18 years, with newly‐diagnosed or relapsed AAV where treatment with cyclophosphamide or RTX is needed; where approved by Regulatory Agencies, adolescents (12 to 17 years) may be enrolled Use of adequate contraception Positive test for anti‐PR3 or anti‐MPO At least 1 major item, or at least 3 non‐major items, or at least the 2 renal items of proteinuria and haematuria on BVAS eGFR ≥15 mL/min/1.73 m² at screening Exclusion criteria Pregnant or breast‐feeding Alveolar haemorrhage requiring pulmonary ventilation support at screening Any other known multi‐system autoimmune disease Required dialysis or plasma exchange within 12 weeks prior to screening Have a kidney transplant Received cyclophosphamide within 12 weeks prior to screening; if on azathioprine, mycophenolate mofetil or MTX at the time of screening, these drugs must be withdrawn prior to receiving the cyclophosphamide or RTX dose on Day 1 Received intravenous glucocorticoids, > 3000 mg methylprednisolone equivalent, within 4 weeks prior to screening Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone‐equivalent for more than 6 weeks continuously prior to screening Received RTX or other B‐cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred (i.e., CD19 count > 0.01 x 10⁹/L); received anti‐TNF treatment, abatacept, alemtuzumab, IVIg, belimumab, tocilizumab, or eculizumab within 12 weeks prior to screening For patients scheduled to receive cyclophosphamide treatment, urinary outflow obstruction, active infection (especially varicella zoster infection), or platelet count <50,000/μL before start of dosing Participated previously in a CCX168 study
Interventions	Experimental: CCX168 (avacopan) Intervention group: CCX168 in combination with RTX or in combination with CPA followed by AZA Active comparator: prednisone
Outcomes	Primary outcomes Remission (Time Frame: 26 weeks) The proportion of patients achieving disease remission assessed by Birmingham Vasculitis Activity Score (BVAS) at Week 26 Sustained remission (Time Frame: 52 weeks) The proportion of patients achieving sustained disease remission assessed by BVAS at Week 52 Secondary Adverse events coded by MedDRA (Time Frame: 60 weeks) Patient incidence of treatment‐emergent serious adverse events, adverse events, and withdrawals due to adverse events Glucocorticoid‐induced toxicity (Time Frame: 26 weeks) Glucocorticoid‐induced toxicity as measured by the Glucocorticoid Toxicity Index Response rapidity (Time Frame: 4 weeks) Remission assessed by BVAS at week 4 Health‐related quality of life (Time Frame: 52 weeks) Change in health‐related quality‐of‐life based on the Short Form‐36 version 2 component and domain scores and the EuroQOL‐5D‐5L visual analogue scale (in mm) and index Estimated glomerular filtration rate (eGFR) (Time Frame: 52 weeks) Change from baseline in eGFR in mL/min/1.73^2 Urinary albumin:creatinine ratio (UACR) (Time Frame: 52 weeks) Change from baseline in UACR in mg/g creatinine Urinary monocyte chemoattractant protein‐1 (MCP‐1):creatinine ratio (Time Frame: 52 weeks) Change from baseline in urinary MCP‐1:creatinine ratio in pg/mg creatinine Vasculitis Damage Index (Time Frame: 52 weeks) Change from baseline in the Vasculitis Damage Index (VDI)
Starting date	December 2016
Contact information	Study Director: Cass Kelleher, MD. ChemoCentryx, Inc.
Notes	Abstract only publication. Recruitment status: Active, not recruiting.

Trial name or title	Alemtuzumab for ANCA Associated Refractory Vasculitis (ALEVIATE)
Methods	Study design: parallel, open‐label RCT Study duration: 6 months Duration of follow‐up: 12 months
Participants	Inclusion criteria Diagnosis of AAV, according to a standardized definition Active vasculitis with at least 1 severe or 3 non‐severe items of BVAS/WG activity (equivalent to BVAS/WG > 3) Previous therapy with either CPA or MTX, in combination with prednisolone for at least 3 months. Exclusion criteria Aged < 18 or > 60 years Creatinine > 150μmol/L (1.7 mg/dL) Total white count < 4 x 10⁹/L or lymphocyte count < 0.5 x 10⁹/L, or IgG < 5g/L, or neutrophil count < 1.5 x 10⁹/L Severe lung haemorrhage with hypoxia (< 85% on room air) Severe gastrointestinal, central nervous system or cardiac vasculitis Previous therapy with: Alemtuzumab at any time IVIg, infliximab, etanercept, adalimumab, abatacept, anti‐thymocyte globulin or plasma exchange in past 3 months; RTX within the past 6 months Intensive care unit requirement Active infection with HIV, hepatitis B or hepatitis C or other infection requiring parenteral or long‐term oral antibiotics History of ITP or platelet count at screening below 50,000 x 10⁶/L Pregnancy or inadequate contraception in pre‐menopausal women Breast feeding Any condition judged by the investigator that would cause the study to be detrimental to the patient. Any other multisystem autoimmune disease including Churg Strauss angiitis, systemic lupus erythematosus, anti‐GBM disease and cryoglobulinaemia Any previous or current history of malignancy (other than resected basal cell carcinoma)
Interventions	Treatment group A Alemtuzumab: high dose (60 mg) 30 mg will be administered on Day 1 and Day 2 at 0 and 6 months Treatment group B Alemtuzumab: low dose (30 mg) 15 mg will be administered on Day 1 and Day 2 at 0 and 6 months
Outcomes	Primary outcomes Proportion of patients with a vasculitis response at 6 months (Time Frame: 6 months) Response includes patients in complete and partial remission. Complete remission (CR) is defined as a BVAS/WG of 0 for at least one month. Partial response (PR) is the absence of severe BVAS/WG items and at least 50% fall in BVAS/WG score from baseline. Proportion of patients with a severe adverse event (Time Frame: 6 months) Secondary outcomes Proportion of patients with treatment failure (Time Frame: 12 months) Treatment failure is defined as the failure to achieve a vasculitis response by six months or a vasculitis relapse between 6 and 12 months Combined damage assessment (CDA) scores (Time Frame: 12 months) Non severe adverse events (Time Frame: 12 months) Cumulative dose of corticosteroids (Time Frame: 12 months) Time to remission (Time Frame: 6 months) Complete and partial Relapse (Time Frame: 12 months) Change in SF‐36 (Time Frame: 12 months)
Starting date	February 2011
Contact information	Dr David Jayne, Cambridge University Hospitals NHS Foundation Trust
Notes	Abstract only publication. Recruitment status: unknown last updated July 2011.

Trial name or title	CMV Modulation of the Immune System in ANCA‐associated Vasculitis (CANVAS)
Methods	Study design: parallel, open‐label RCT Study duration: not reported Duration of follow‐up: 12 months
Participants	Country: UK Setting: single centre Patients with documented diagnosis of granulomatosis with polyangiitis (Wegener), microscopic polyangiitis or renal limited vasculitis according to Chapel Hill Consensus Conference Criteria; in stable remission (no documented clinical disease activity) for at least 6 months prior to study entry; on maintenance immunosuppression with prednisolone, MMF or AZA alone or in combination (maximum two agents); documented past evidence (any time point) of CMV infection (CMV‐specific immunoglobulin G detected in peripheral blood); documentation that female patients of child‐bearing potential are not pregnant and are using an appropriate form of contraception; written informed consent for study participation Number: 50 Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: stage 5 CKD (eGFR <1 5 mL/min/1.73 m²); tests performed within 6 months of pre‐baseline visit can be used for this assessment; other significant chronic infection (HIV, hepatitis B, hepatitis C or tuberculosis); B‐cell depleting therapy within 12 months or T‐cell depleting therapy within 6 months; treatment with anti‐CMV therapies in the last month; underlying medical conditions, which in the opinion of the investigator place the patient at unacceptably high risk for participating in the study Inability to participate fully or appropriately in the study
Interventions	Treatment group Valaciclovir: 2 g, 4 times/day for 6 months. dose adjusted for kidney function Control group No additional treatment
Outcomes	Proportion of patients with CMV reactivation on quantitative PCR on blood and urine Change in proportion of CD4+CD28‐ cells Arterial stiffness, carotid to femoral pulse wave velocity Change in blood pressure Peripheral blood CD4+CD28‐ T cells analysed at baseline and 6 months IFN‐a and TNF‐a production with CMV lysate measured Persistence of effect of valaciclovir on T cells 6 months after treatment Change in the immune phenotype of CD4+ T cells Soluble markers on inflammation. Concentration of IL‐2, tumour necrosis factor alpha (TNF‐Î±), IFN‐Î³, IL‐6, IL‐10, IL‐17 and highly sensitive C‐reactive protein (CRP) in peripheral blood soluble markers of endothelial damage. Concentration of fractalkine, IP‐10, regulated on activation, normal T cell expressed and secreted (RANTES), P‐selectin, E‐selectin, monocytechemoattractant protein‐1 (MCP‐1), soluble vascular cell adhesion molecule 1 (sVCAM‐1) and soluble intracellular cell adhesion molecule 1 (sICAM‐1) in peripheral blood
Starting date	4 July 2012
Contact information	Professor Lorraine Harper, University of Birmingham
Notes	Funding source: WT and Vasculitis UK Protocol and abstract‐only publications