Interventions for renal vasculitis in adults

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

doi:10.1002/14651858.CD003232.pub4

Intervenciones para la vasculitis renal en adultos

Declaraciones de intereses de los autores

Versión publicada: 13 enero 2020 Historial de versiones

https://doi.org/10.1002/14651858.CD003232.pub4

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Resumen

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Antecedentes

La vasculitis renal se presenta como glomerulonefritis rápidamente progresiva y comprende un grupo de trastornos caracterizados por insuficiencia renal aguda (IRA), hematuria y proteinuria. El tratamiento de estos trastornos incluye corticosteroides y agentes no esteroideos en combinación con recambio plasmático. Aunque la inmunosupresión en general ha sido muy exitosa en el tratamiento de estos trastornos, quedan sin responder muchas preguntas en cuanto a la dosis y la duración del tratamiento, el uso del recambio plasmático y la función de los nuevos tratamientos. Esta publicación de 2019 es una actualización de una revisión publicada por primera vez en 2008 y actualizada en 2015.

Objetivos

Evaluar los efectos beneficiosos y perjudiciales de cualquier intervención utilizada para el tratamiento de la vasculitis renal en adultos.

Métodos de búsqueda

Se realizaron búsquedas en el registro de estudios del Grupo Cochrane de Riñón y Trasplante hasta el 21 septiembre 2019, mediante contacto con el especialista en información, con los términos de búsqueda relevantes para esta revisión. Los estudios en el registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, en actas de congresos, en el International Clinical Trials Register (ICTRP) Search Portal, y en ClinicalTrials.gov.

Criterios de selección

Ensayos controlados aleatorizados que examinaron cualquier intervención para el tratamiento de la vasculitis renal en adultos.

Obtención y análisis de los datos

Dos autores de la revisión evaluaron de forma independiente la calidad de los estudios y extrajeron los datos. Los análisis estadísticos se realizaron mediante el uso de un modelo de efectos aleatorios y los resultados se expresaron como riesgo relativo (RR) con intervalos de confianza (IC) del 95% para los resultados dicotómicos o diferencia de medias (DM) para los resultados continuos.

Resultados principales

Se incluyeron 40 estudios (3764 pacientes). Los primeros estudios realizados tendieron a presentar un mayor riesgo de sesgo debido al diseño deficiente del estudio (o al informe deficiente), los amplios criterios de inclusión, las definiciones de la enfermedad poco sólidas y el reducido número de pacientes. Los estudios posteriores tendieron a mejorar en todas las áreas de calidad, ayudados por el desarrollo de grandes grupos de estudio transnacionales.

Tratamiento de inducción: El intercambio de plasma como tratamiento adyuvante puede reducir la necesidad de diálisis a los tres meses (2 estudios: RR 0,43; IC del 95%: 0,23 a 0,78; I² = 0%) y 12 meses (6 estudios: RR 0,45; IC del 95%: 0,29 a 0,72; I² = 0%) (evidencia de certeza baja). El recambio plasmático puede llevar a poca o ninguna diferencia en cuanto a la muerte, la creatinina sérica (CrS), la remisión sostenida o el número total o grave de eventos adversos. El intercambio de plasma puede aumentar el número de infecciones graves (5 estudios: RR 1,26; IC del 95%: 1,03 a 1,54; I² = 0%) (evidencia de certeza baja). Las tasas de remisión para la ciclofosfamida en pulsos versus continua fueron equivalentes, aunque la primera modalidad puede aumentar el riesgo de recurrencia (4 estudios): RR 1,79; IC del 95%: 1,11 a 2,87; I² = 0%) (evidencia de certeza baja) en comparación con la ciclofosfamida continua. La ciclofosfamida en pulsos puede resultar en poca o ninguna diferencia en la muerte en el seguimiento final o la CrS en cualquier momento. Más pacientes requirieron diálisis en el grupo de ciclofosfamida en pulsos. La leucopenia fue menos común con el tratamiento en pulsos; sin embargo, las náuseas fueron más frecuentes. El rituximab comparado con la ciclofosfamida probablemente resulta en poca o ninguna diferencia en cuanto a la muerte, la remisión, la recurrencia, los eventos adversos graves, las infecciones graves o los eventos adversos graves. No se informó sobre la función renal ni la diálisis. Un estudio individual no informó de diferencias en el número de muertes, la necesidad de diálisis o los eventos adversos entre el micofenolato mofetilo (MMF) y la ciclofosfamida. Se informó que la remisión mejoró con el MMF; sin embargo, un mayor número de pacientes presentó recurrencias. Una dosis inferior de corticosteroides fue probablemente tan efectiva como la dosis alta y puede ser más segura, con menos infecciones; no se informó ni la función renal ni la recurrencia. Hubo poca o ninguna diferencia en la muerte o la remisión con el tratamiento de entre seis y 12 pulsos de ciclofosfamida. Hay evidencia de certeza baja de que hubo menos recurrencias con 12 pulsos (2 estudios: RR 1,57; IC del 95%: 0,96 a 2,56; I² = 0%), pero más infecciones (2 estudios: RR 0,79; IC del 95%: 0,36 a 1,72; I² = 45%). Un estudio informó que los eventos adversos graves fueron menores en los pacientes que recibieron seis, en comparación con 12 pulsos de ciclofosfamida. No se informó sobre la función renal ni la diálisis. Hay evidencia limitada de estudios únicos sobre la efectividad de la inmunoglobulina intravenosa, el avacopán, el metotrexato, la inmunoadsorción, la linfocitaféresis o el etanercept.

Tratamiento de mantenimiento: La azatioprina tiene una eficacia equivalente como agente de mantenimiento a la de la ciclofosfamida, con menos episodios de leucopenia. El MMF resultó en una tasa de recaída mayor cuando se estudió en comparación con la azatioprina en el mantenimiento de la remisión. El rituximab es un agente efectivo de inducción de remisión y mantenimiento. El cotrimoxazol oral no redujo significativamente las recurrencias en la granulomatosis con poliangiitis. Hubo menos recurrencias pero más eventos adversos graves con la leflunomida en comparación con el metotrexato. Hay evidencia limitada de estudios individuales acerca de la efectividad del metotrexato versus ciclofosfamida o azatioprina, ciclosporina versus ciclofosfamida, azatioprina extendida versus estándar y belimumab.

Conclusiones de los autores

El recambio plasmático es efectivo en los pacientes con IRA grave secundaria a la vasculitis. La ciclofosfamida en pulsos da lugar a un mayor riesgo de recurrencia en comparación con la administración oral continua, pero con una reducción en la dosis total. Aunque la ciclofosfamida es el tratamiento de inducción estándar, el rituximab y el MMF también fueron efectivos. La azatioprina, el metotrexato y la leflunomida fueron efectivos como tratamiento de mantenimiento. Se necesitan estudios adicionales para delinear más claramente el lugar apropiado de los agentes más nuevos en una estrategia terapéutica basada en la evidencia.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Intervenciones para la vasculitis renal en adultos

¿Cuál es el problema?
La vasculitis renal es una forma rápidamente progresiva de nefropatía que causa daño a las estructuras pequeñas (glomérulos) del riñón, encargadas de filtrar los desechos y líquidos de la sangre para formar la orina. La enfermedad produce una pérdida rápida de la función renal. Se recomiendan los corticosteroides y la ciclofosfamida para ayudar a suprimir el sistema inmunitario.

¿Qué se hizo?
Se realizaron búsquedas de ensayos controlados aleatorizados que investigaran cualquier intervención para el tratamiento de la vasculitis renal en adultos, en el Registro Cochrane de Estudios de Riñón y Trasplante hasta el 21 de noviembre 2019.

¿Qué se encontró?
Se identificaron 40 estudios (3764 pacientes). El recambio plasmático reduce el riesgo de insuficiencia renal terminal en los pacientes con insuficiencia renal aguda grave. La administración de ciclofosfamida en pulsos produce tasas de remisión adecuadas pero un mayor riesgo de recurrencia. Otros agentes de inducción apropiados incluyen el rituximab y el micofenolato. La azatioprina es efectiva como tratamiento de mantenimiento una vez que se logró la remisión. Una dosis más baja de corticosteroides es tan efectiva como una dosis alta y puede ser más segura, con menos infecciones. Un estudio muestra que se puede utilizar un nuevo inhibidor del complemento para reemplazar los corticosteroides en el tratamiento inicial de la vasculitis. Estos son datos iniciales. Es probable que el medicamento sea muy caro, por lo que su lugar en el tratamiento aún no está claramente definido. El micofenolato mofetilo también se ha probado en el tratamiento de mantenimiento y se encontró que da lugar a una tasa mayor de recurrencia de la enfermedad en comparación con la azatioprina. El metotrexato y la leflunomida son útiles en el tratamiento de mantenimiento, aunque no se ha definido claramente la efectividad relativa. Los pacientes con inmunosupresión hasta cuatro años después del diagnóstico tienen una tasa de recurrencia menor a la de aquellos en que el tratamiento se suspende por tres años.

Conclusiones
El intercambio de plasma fue efectivo en pacientes con IRA grave. La ciclofosfamida en pulsos da lugar a un mayor riesgo de recurrencia en comparación con la administración oral continua, pero con una reducción en la dosis total. Aunque la ciclofosfamida es el tratamiento de inducción estándar, el rituximab y el micofenolato mofetilo también fueron efectivos. Los corticosteroides en dosis más bajas ahora pueden ser usados con seguridad en los protocolos de tratamiento inicial. La azatioprina, el rituximab, el micofenolato, el metotrexato y la leflunomida son tratamientos de mantenimiento efectivos. Se requieren más ensayos para comprender estos fármacos y tratamientos nuevos para atender rápidamente la vasculitis renal.

Authors' conclusions

Implications for practice

Plasma exchange is effective in patients with severe AKI secondary to vasculitis. It is not yet clear whether the results of the PEXIVAS study alter this conclusion. On current data, the use of pulse CPA results in an increased risk of relapse when compared to continuous use but a reduced total CPA dose. Rituximab and MMF are comparable to CPA as induction agents. IVIg is useful but only as a short‐term measure. The PEXIVAS protocol for lower dose glucocorticoid induction treatment appears to be safer than the higher dose with equivalent efficacy for remission induction.

AZA and MTX are effective as maintenance therapy once remission has been achieved. The use of MMF in remission maintenance should be third line after failure, or contraindication, of other agents such as AZA and MTX. Rituximab is a superior agent to AZA for maintenance treatment. The use of fixed interval dosing of rituximab may be more efficacious than tailored interval dosing but requires further study. Patients are likely to benefit from at least four years immunosuppression post diagnosis of renal vasculitis.

The use of co‐trimoxazole is not supported for prevention of relapse of vasculitis. Etanercept and belimumab are not recommended for use in vasculitis. Leflunomide may be useful as maintenance therapy but requires further evaluation.

Implications for research

The exact place of plasma exchange in the treatment of vasculitis requires further analysis of the huge dataset behind the PEXIVAS study. Clarity is required over the effect of treatments within the first 12 months of treatment. Whilst the "hard endpoints" at the end of the study are of great clinical and administrative concern, patients will find an extra 6 months alive and off dialysis of significant benefit. Also the use of plasma exchange in pulmonary haemorrhage has not been finally clarified.

The optimal dose of steroids to be used in induction treatment requires further study. Can the PEXIVAS study lower dose be halved without loss of efficacy? Should steroid treatment be more "front‐loaded" with a higher percentage of the dose being given in the first 2 to 4 weeks of treatment with a more rapid dose reduction? Previously the currently side‐lined MEPEX study clearly showed improved outcomes with plasma exchange rather than methylprednisolone. Should the first two weeks of prednisolone be replaced with alternate day plasma exchange with or without a complement inhibitor?

The data from the MAINRITSAN study seem to confirm previous findings that the use of pulse CPA induction therapy increase the risk of subsequent relapse. Whilst this was an appropriate strategy to increase the event rate in this study, it also gave a relapse rate that was no improvement upon the rate achieved in the IMPROVE study with induction using oral CPA and maintenance with AZA. The IMPROVE study regimen would then be the cheaper option for countries unable to access rituximab treatment. Studies are required that examine the long term effects of the main induction regimens (now oral and pulse CPA, rituximab and MMF) on both remission and relapse rate. One hypothesis would be that there are optimal induction/maintenance combinations that are likely to give equivalent outcomes over the longer term.

The use of AVACOPAN in treatment protocols needs further research. An initial study using the drug as steroid replacement has been successful, but this currently seems an unlikely clinical strategy in the short term due to clinicians' familiarity with steroids and their very low price. Equivalence with glucocorticoid seems unlikely to be an adequate reason for complement inhibitors to feature significantly in treatment protocols in vasculitis.

The AVACOPAN study does illustrate that the strategy of comparing gold standard treatment with a new treatment is potentially more likely to reveal new treatment modalities rather than the adjunctive treatment approach where gold standard therapy is given to both treatment arms and the new therapy is added. The etanercept and belimumab studies are "adjunctive therapy" approaches that have failed. The Avacopan study approach requires more courage, more complex ethical consideration and, potentially, a graded experimental design but may be more likely to be successful.

The studies in this review reflect the solid success of the collaborative efforts of the vasculitis networks which have culminated in the recent PEXIVAS study. Building on this success will hopefully continue to provide answers to the many questions remaining.

Summary of findings

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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.
¹ Though some of the studies are of high quality, others have very significant problems (e.g. Mauri 1985; Pusey 1991) ² Event rate and sample size are small 3 High heterogeneity across groups

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

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.
¹ Two of these studies had a high risk of bias. ² Sample size and/or event rate were low. ³ Wide 95% CI ⁴ Very different event rates across studies

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

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.
¹ Number of events overall is low ² One small study ³ Different event rates in the 2 studies

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

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.
¹ Single study results ² Wide CI ³ Some inconsistency in results between studies

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

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.
¹ Small sample size; single study results ² Wide CI

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Summary of findings 6. Azathioprine versus cyclophosphamide for maintenance therapy

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.
¹ Single study results ² Wide CI

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Summary of findings 7. Azathioprine versus methotrexate for maintenance therapy

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.
¹ Single study results ² Wide CI

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Summary of findings 8. Antibiotics versus placebo for maintenance therapy

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.
¹Downgrade 2 levels for study size and limitations with risk of bias assessment ² One study had multiple limitations in the reporting of the study design ³ Two small studies

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Summary of findings 9. Leflunomide versus methotrexate for maintenance therapy

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.
¹Downgrade 2 levels for study size and limitations with risk of bias assessment * Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group

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

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. The Register contains studies identified from the following sources.

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.

Figure 1

Study flow diagram

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.

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

Remission induction studies

1: Plasma exchange as adjunctive therapy

Ten studies investigated plasma exchange as adjunctive therapy (Cole 1992; Glockner 1988; Mauri 1985; MEPEX 2007; PEXIVAS 2013; Pusey 1991; Rifle 1980; Stegmayr 1999; Szpirt 2011; Zauner 2002). Zauner 2002 contained no extractable data and could not be included in the meta‐analyses.

Plasma exchange may reduce the need for KRT at three months (Analysis 1.3.2 (2 studies, 147 participants): RR 0.43, 95% CI 0.23 to 0.78; I² = 0%; NNT = 5; low certainty evidence) and 12 months (Analysis 1.3.4 (6 studies, 235 participants): RR 0.45, 95% CI 0.29 to 0.72; I² = 0%; NNT = 5; low certainty evidence) post‐treatment. The MEPEX 2007 included patients with SCr > 500 µM and reported a reduction in the need for dialysis at three and 12 months. A subgroup analysis included in Pusey 1991 showed that plasma exchange is effective in patients with severe AKI requiring dialysis. PEXIVAS 2013 reported no difference in the need for dialysis at any time point (Analysis 1.3.6). Currently there are no data available at specific time points for PEXIVAS 2013.

Plasma exchange may increase the number of serious infections compared to control (Analysis 1.5.1 (5 studies, 956 participants): RR 1.26, 95% CI 1.03 to 1.54; I² = 0%; low certainty evidence).

Plasma exchange may make little or no difference to death (Analysis 1.1), SCr (Analysis 1.2), sustained remission (Analysis 1.4), serious or total number of adverse events (Analysis 1.5.7; Analysis 1.5.8) (low certainty evidence).

2: Pulse versus continuous cyclophosphamide

Four studies (Adu 1997; Guillevin 1997; Haubitz 1998; CYCLOPS 2004) investigated the use of pulse and continuous administration of CPA for remission induction. Patients with systemic, rather than specifically renal, vasculitis were included in these studies. Raw data has been obtained from Adu 1997 and those patients with PAN have been excluded from these analyses.

Compared to continuous CPA, pulse CPA may make little or no difference to death at final follow‐up (Analysis 2.1.5 (4 studies, 278 participants): RR 0.77, 95% CI 0.44 to 1.32; I² = 15%; low certainty evidence) or SCr at any time point (Analysis 2.2).

There were more patients requiring KRT at the end of the study period in the pulse CPA group than the continuous CPA group however further studies are required (Analysis 2.3.4 (4 studies, 245 participants): RR 1.90, 95% CI 0.92 to 3.91; I² = 0%; low certainty evidence).

Pulse CPA may make little or no difference to remission compared to continuous CPA (Analysis 2.4).

Pulse CPA may increase the risk of relapse compared to continuous CPA at the end of follow‐up (Analysis 2.5.3 (4 studies, 235 participants): RR 1.79, 95% CI 1.11 to 2.87; I² = 0%; NNH = 5; low certainty evidence).

Leukopenia was less common with pulse treatment (Analysis 2.7.2 (4 studies, 278 participant): RR 0.53, 95% CI 0.36 to 0.77; I² = 0%; NNH = 5), however nausea was more common (Analysis 2.7.3 (2 studies, 97 participants): RR 2.51, 95% CI 1.07 to 5.89; I² = 0%; NNH = 7).

Pulse CPA compared to continuous CPA may make little or no difference to either treatment failure (Analysis 2.6) or serious infections (Analysis 2.7.1).

3: Rituximab versus cyclophosphamide

Two studies compared rituximab versus CPA for remission induction (RAVE 2010; RITUXVAS 2010).

Rituximab compared to CPA probably makes little or no difference to death (Analysis 3.1), remission (Analysis 3.2), relapse (Analysis 3.3), severe adverse events (Analysis 3.4.1), serious infections (Analysis 3.4.2), or severe adverse events (episodes/patient‐months) (Analysis 3.5).

Kidney function and dialysis were not reported.

4: Mycophenolate mofetil versus cyclophosphamide

Three studies compared MMF and CPA for remission induction (Han 2011b; Hu 2008b; MYCYC 2012).

MYCYC 2012 reported 5/70 deaths in the MMF group and 4/70 in the CPA group (Analysis 4.1). Two patients in each group required dialysis at six months (Analysis 4.2).

MMF improved remission at six months compared to CPA (Analysis 4.3.1 (3 studies, 217 participants): RR 1.17, 95% CI 1.01 to 1.35; I² = 4%; high certainty evidence).

MYCYC 2012 reported more patients relapsed with MMF (21/63) than CPA (12/56) at 18 months (Analysis 4.4).

There were no differences in adverse events (GI symptoms, infections, leukopenia, serious adverse events) between the two groups (Analysis 4.5).

Kidney function was not reported.

5: Methotrexate versus cyclophosphamide

NORAM 2005 compared MTX with CPA.

There were no deaths in the MTX group at 6 months and 1/49 deaths in the CPA group. There were two deaths in each group at 18 months (Analysis 5.1)

Remission at 6 months was similar (MTX: 44/49; CPA: 43/46) (Analysis 5.2.1). The authors reported longer time to remission for MTX in patients with a higher disease activity index. Relapse post‐remission rates were higher for the MTX group (32/46) than the CPA group (20/43) (Analysis 5.3). Relapse figures quoted here are end of study numbers, not a specific time point.

Adverse event rates were reported to be similar with leukopenia more frequent with CPA treatment (6 events in the CPA group and 0 events in the MTX group) and more liver dysfunction in MTX (7 events in the MTX group and 1 in the CPA group).

Kidney function and dialysis were not reported.

6: Avacopan versus prednisolone

CLEAR 2013 reported the mean eGFR at three months for patients receiving avacopan was 56.1 ± 5.2 mL/min/1.73 m² and 52.8 ± 3.6 mL/min/1.73 m² for those receiving prednisolone (Analysis 6.2). There were no deaths reported in either group (Analysis 6.1)

Remission (avacopan: 7/21; prednisolone: 8/20) (Analysis 6.3) and relapse (avacopan: 3/22; prednisolone: 2/23) (Analysis 6.4) were similar.

There were more serious adverse events in the avacopan group (avacopan: 8/22; prednisolone: 4/23) (Analysis 6.5).

Dialysis was not reported.

7: Intravenous immunoglobulin use in persistent disease

Jayne 2000 reported the use of IVIg demonstrated a therapeutic response in more patients at three months when compared with placebo. Response was defined as a reduction in BVAS of > 50% (IVIg: 14/17; control: 6/17) Analysis 7.2. Benefit was not demonstrated beyond three months. There were no deaths in the IVIg group and 2/17 deaths in the control group (Analysis 7.1). There were 5/16 relapses in the IVIg group and 4/15 in the control group (Analysis 7.3). There were more adverse events in the IVIg group (IVIg: 12/17; control: 4/17) (Analysis 7.4).

Kidney function and dialysis were not reported.

8: Immunoadsorption versus plasma exchange

Stegmayr 1999 reported 3/21 deaths in the immunoadsorption group and 2/23 deaths in the plasma exchange group (Analysis 8.1).

At six months SCr was 164.5 ± 94.1 µmol/L in the immunoadsorption group and 187.8 ± 61.2 µmol/L in the plasma exchange group (Analysis 8.2). Two of 18 needed dialysis in the immunoadsorption group and 3/21 in the plasma exchange group (Analysis 8.3).

Remission, relapse, and adverse events were not reported.

9: Lymphocytapheresis

Furuta 1998 reported a reduction in SCr with lymphocytapheresis (2.1 ± 0.3 mg/dL) compared to control (4.2 ± 0.9 mg/dL) at four weeks (Analysis 9.2). There were 2/12 deaths in the lymphocytapheresis group and 5/12 in the control group (Analysis 9.1). One of 12 patients required dialysis in the lymphocytapheresis group and 3/12 in the control group (Analysis 9.3).

Remission, relapse, and adverse events were not reported.

10: Duration (6 versus 12 pulses) of cyclophosphamide induction

Two studies compared six versus 12 pulses of cyclophosphamide for remission induction (CORTAGE 2015; Guillevin 2003).

Guillevin 2003 reported 6/19 deaths in the 6‐pulse group compared to 6/28 in the 12‐pulse group at the end of the study. CORTAGE 2015 reported 9/53 deaths in the 6‐pulse group and 12/53 in the 12‐pulse group at 3 years (Analysis 10.1).

There was little or no difference in remission between 6 and 12 pulses of CPA (Analysis 10.2 (2 studies, 151 participants): RR 0.99, 95% CI 0.85 to 1.15; I² = 11%; low certainty evidence). There is low certainty evidence that there were less relapses with 12 pulses (Analysis 10.3 (2 studies, 133 participants): RR 1.57, 95% CI 0.96 to 2.56; I² = 0%), but more infections (Analysis 10.4.1 (2 studies, 169 participants): RR 0.79, 95% CI 0.36 to 1.72; I² = 45%).

CORTAGE 2015 reported severe adverse events were less in patients receiving 6 (32/53) compared to 12 pulses (40/51) of CPA (Analysis 10.4.2).

Kidney function and dialysis were not reported.

11: Reduced versus standard dose steroids

PEXIVAS 2013 reported 46/353 death in the reduced dose group and 53/351 in the standard dose group (Analysis 11.1). There were 70/353 requiring dialysis in the reduced dose group and 68/351 in the standard dose group (Analysis 11.2).

In the reduce dose group 204/353 had sustained remission and there were 193/353 in the standard dose group (Analysis 11.3).

There were 231/353 severe adverse events and 96/353 serious infections in the reduced dose group and 218/351 and 116/351 in the standard dose group (Analysis 11.4.1) (Analysis 11.4.2).

Kidney function and relapse were not reported.

12: Etanercept versus placebo

WGET 2002 reported 4/89 deaths in the etanercept group and 2/85 in the placebo group (Analysis 12.1). There were 62/89 sustained remissions in the etanercept group and 64/85 in the placebo group (Analysis 12.2); 19/62 relapses in the etanercept group and 21/64 in the placebo group (Analysis 12.3). There were 44/89 infections and 6/89 cancers in the etanercept group and 42/85 and 0/85 in the placebo group (Analysis 12.4).

Kidney function and relapse were not reported.

Maintenance therapy studies

13: Azathioprine versus cyclophosphamide

CYCAZAREM 2003 reported there were 37/71 relapses after the introduction of AZA compared to 26/73 for the group who remained on CPA (Analysis 13.3). There were 35 episodes/1095 patient‐months of leukopenia reported in patients treated with CPA and 22 episodes/1065 patient‐months in the AZA group (Analysis 13.5.1).

Leukopenia was more frequent in the CPA group (35/73) compared to the AZA group (22/71) (Analysis 13.5) but no difference in infection (AZA: 13/71; CPA: 13/73) (Analysis 13.5.2) or serious adverse events (AZA: 8/71; CPA: 7/73) (Analysis 13.4.3).

Long‐term follow‐up (median time 8.5 years) showed no difference in death (AZA: 9/71; CPA: 12/73) (Analysis 13.1.1) or need for dialysis (AZA: 8/71; CPA: 5/73) Analysis 13.2).

Kidney function was not reported.

14: Mycophenolate mofetil versus azathioprine

IMPROVE 2003 reported no difference in death (Analysis 14.1) between MMF (1/76) and AZA (1/80). More patients were reported to relapse in the MMF group (42/76) compared to the AZA group (30/80) (Analysis 14.2.1). There were no differences between major (Analysis 14.2.2) and minor relapses (Analysis 14.2.3). In the MMF group there were 3/76 serious infections and 8/80 in the AZA group (Analysis 14.3.2). In the MMF group there 4/76 reports of leukopenia and 7/80 reports in the AZA group (Analysis 14.3.3).

Kidney function and dialysis were not reported.

15: Azathioprine versus methotrexate

WEGENT 2008 reported no differences between the treatments for death (AZA: 0/63; MTX: 1/63) (Analysis 15.1), relapse (AZA: 23/63; MTX: 21/63) (Analysis 15.2), and event‐free survival (AZA: 17/24; MTX: 15/25) (Analysis 15.4).

There were more patients with relapse‐free survival at 18 (AZA: 30/43; MTX 40/43) and 24 months (AZA: 13/25; MTX: 22/30) in the MTX group (Analysis 15.3) but not at 36 months. There were more adverse events (AZA: 26/63; MTC: 35/63) (Analysis 15.5.1), severe adverse events (AZA: 5/63; MTX: 11/63) (Analysis 15.5.2), and adverse events causing death or study drug withdrawal (AZA: 7/63; MTTX: 12/63) (Analysis 15.5.2) in the MTX group.

Kidney function and dialysis were not reported.

16: Rituximab versus azathioprine

MAINRITSAN 2014 reported less major relapses in rituximab compared to azathioprine at one year (RTX: 1/57; AZA: 8/58) (Analysis 16.2.1), two years (RTX: 1/59; AZA: 10/58) (Analysis 16.2.2), and 28 months (RTX: 3/57; AZA: 17/58) (Analysis 16.2.3).

No differences were found between the two treatments for death (Analysis 16.1), minor relapse at 12, 24 and 28 months (Analysis 16.3), or serious infection (Analysis 16.4).

Kidney function and dialysis were not reported.

17: Co‐trimoxazole (antibiotics) versus placebo for relapse prevention

Two studies investigated co‐trimoxazole for relapse prevention (Stegeman 1996; Zycinska 2009). Stegeman 1996 reported death at six months and remission at 12 and 24 months; Zycinska 2009 reported remission at 12 and 18 months.

Stegeman 1996 reported no difference in death at six months (Analysis 17.1).

At 12 months antibiotics may make little or no difference to remission (Analysis 17.2.1 (2 studies, 111 participants): RR 1.14, 95% CI 0.98 to 1.33; I² = 0%; low certainty evidence).

Zycinska 2009 reported no improvement in remission at 18 months (antibiotics: 12/16; placebo: 8/15) (Analysis 17.2.2) and Stegeman 1996 reported no improvement at 24 months (antibiotics: 31/41; placebo: 23/39) (Analysis 17.2.3).

Stegeman 1996 reported more adverse events causing study drug discontinuation (antibiotics: 8/41; placebo: 2/40) (Analysis 17.3.6).

There were some significant difficulties with the reporting of Zycinska 2009 along with unbalanced groups at baseline which would bias in favour of the treatment being effective.

Kidney function and dialysis were not reported.

18: Cyclosporin versus cyclophosphamide

Szpirt 2011 reported no difference in the number of relapses with cyclosporin (10/16) compared to CPA (8/16) (Analysis 18.1).

Death, kidney function, dialysis, remission, adverse events, and infection were not reported.

19: Extended versus standard azathioprine

Two studies compared an extended azathioprine with a standard AZA treatment (AZA‐ANCA 2016; REMAIN 2003). There were more relapses in the standard AZA group (Analysis 19.3 (2 studies, 162 participants): RR 0.41, CI 0.26 to 0.64).

No differences were found for death between the two groups (Analysis 19.1). REMAIN 2003 reported 0/61 in the extended AZA group and 4/56 in the standard AZA group needed dialysis (Analysis 19.2).

AZA‐ANCA 2016 reported no differences in serious infections (Analysis 19.4.1) and leukopenia (Analysis 19.4.2) between the two treatments.

Kidney function was not reported.

20: Leflunomide versus methotrexate

Metzler 2007 reported more relapses in the MTX group (13/28) compared to the leflunomide group (6/26) (Analysis 20.1.1). More major relapses were also reported in the MTX group (7/28) compared to the leflunomide group (1/26) (Analysis 20.1.2). There were more severe adverse events in the leflunomide group (5/26) than the MTX group (0/28) (Analysis 20.2.1). There were no differences between the groups for infection (Analysis 20.2.2) or leukopenia (Analysis 20.2.3).

There were multiple methodological difficulties with this study addressed in the discussion section.

Death, kidney function, and dialysis were not reported.

21: Methotrexate versus cyclophosphamide

Maritati 2017 reported no differences in death (Analysis 21.1), relapse (Analysis 21.2.1), major relapse (Analysis 21.2.2), minor relapse (Analysis 21.2.3), or serious infection (Analysis 21.3.1) at 12 months. Leukopenia was more frequent in the CPA group (7/33) compared to the MTX group (3/38) (Analysis 21.3.2)

Kidney function and dialysis were not reported.

22: Tailored versus fixed rituximab

MAINRITSAN 2 2018 compared a tailored schedule of 500 mg rituximab infusion with a fixed schedule of 500 mg rituximab infusion and reported no differences for death (Analysis 22.1) and serious infection (Analysis 22.3.2) at 18 months. There were 6/81 major relapses in the tailored group and 3/81 in the fixed group (Analysis 22.2) and 26/81 serious adverse events in the tailored group and 31/81 in the fixed group (Analysis 22.3.1).

Kidney function and dialysis were not reported.

23: Pre‐emptive therapy for relapse

Two studies investigated pre‐emptive therapy for relapse (Boomsma 2003; Tervaert 1990).

For patients with a rising ANCA, fewer relapses occur for those randomised to increased immunosuppression in both studies (Analysis 23.1 (2 studies, 60 participants): RR 0.23, 95% CI 0.03 to 1.59; I² = 53%).

Death, kidney function, dialysis, adverse events, and infection were not reported.

24: Belimumab versus placebo

BREVAS 2019 compared belimumab to placebo and reported no difference to relapse (Analysis 24.1), any adverse event (Analysis 24.2.1) or infection (Analysis 24.2.2).

Death, kidney function, and dialysis were not reported.

Discussion

Summary of main results

In this 2019 review update, an additional nine studies have been included since the 2015 update (a total of 40 studies, 3764 participants).

Remission induction

Plasma exchange as adjunctive therapy

This meta‐analysis shows that plasma exchange confers a significant benefit to many patients with RPGN by reducing the risk of ESKD at both three and 12 months from diagnosis. Szpirt 2011 supports this effect and also suggests that the benefit may be present at five years follow‐up. The 12‐month RR of 0.45 suggests that the number of patients requiring dialysis may be halved by this intervention. Previous studies have shown an effect in the most severely ill patients. A subgroup analysis in Pusey 1991 showed a benefit for patients requiring dialysis at presentation. More recently, MEPEX 2007 has shown a benefit for patients with SCr > 500 µM with ANCA‐associated vasculitis. The majority of patients included in these studies would meet the criteria for having severe AKI (SCr > 500 µM or dialysis required at presentation). It is therefore not clear whether plasma exchange has any impact in patients whose kidney failure is not severe. There was little statistical heterogeneity in all outcomes of these studies with the single exception of SCr at 12 months. Whilst the PEXIVAS results have been included in the review, they do not directly impact the outcomes at particular time points. At time of writing the final manuscript is not released and no data are available to the authors to enter data appropriately. The survival curves published suggest that there is an early effect of plasma exchange on the combined end point of death and dialysis but this has yet to be clarified by the research team. Currently the detailed evidence continues to suggest an effect of plasma exchange on reducing the requirement for dialysis treatment.

Pulse versus continuous cyclophosphamide

Pulse treatment with CPA was equivalent to continuous treatment for remission induction, but may increase the risk of relapse at the end of follow‐up. None of the studies were powered to answer the question of relapse rate since this would require either much larger studies or significantly longer follow‐up. We are therefore reliant on the results of meta‐analysis to attempt to provide an answer. This answer is less than perfect since it is a meta‐analysis of results at different times post treatment across studies with significantly different protocols. In spite of this, there is no evidence of heterogeneity in the outcome, suggesting that the final result is likely to be valid. This analysis is supported by the recent follow‐up data from CYCLOPS 2004 showing that patients treated with pulse CPA suffered a 39.5% relapse rate as opposed to 19.8% for continuous daily treatment. Though the rates of relapse with pulse CPA treatment are perhaps discouraging, this does not invalidate this mode of treatment. Pulse therapy still delivers a significantly lower total dose of CPA. For those patients who remain in remission, they have likely benefited in terms of risk of long term side effects. The MAINRITSAN study has unexpectedly provided an interesting insight into the increased relapse rate with pulse therapy. This has been the only study to date that has utilised only pulse cyclophosphamide for induction treatment. Patients were then randomised to rituximab or azathioprine for maintenance, with the study showing an improved relapse rate on rituximab. However, the overall rate of relapse in the rituximab limb was similar to the rate in the azathioprine limb of the IMPROVE study. The IMPROVE study patients were treated with oral cyclophosphamide for induction. This shows that relapse rate is highly dependent on the induction treatment, as well as the maintenance therapy used.

There is a trend towards more patients requiring dialysis with the use of pulse CPA therapy. This is currently not statistically significant, but the fact remains that there were twice as many patients requiring dialysis after pulse therapy and that this effect is present in all studies. This effect was not confirmed in the long term follow‐up of CYCLOPS 2004. CPA treatment was given for three months, approximately six months, one and two years in the four relevant studies. This difference may account for the significant level of statistical heterogeneity detected in death and the incidence of serious infections. Pulse therapy also caused significantly more nausea but less leukopenia and serious infections. In the light of data from CYCAZAREM 2003, it would seem reasonable to suggest that continuous oral CPA should be limited to three months treatment if the patient has achieved a sustained remission with a change to AZA for maintenance therapy. The optimal regimen for CPA administration for remission induction in ANCA‐associated vasculitis remains unclear.

Rituximab versus cyclophosphamide alone for remission induction

RITUXVAS 2010 and RAVE 2010 are two well‐designed studies showing that Rituximab is equivalent to CPA therapy for remission induction whilst side effects occur at a similar frequency, albeit possibly in a smaller number of patients with rituximab. The difference in remission rates of over 90% in RITUXVAS 2010 and 605 to 70% in RAVE 2010 at six months is of interest. The studies differed in their patient population (new versus new and relapsed), treatment protocols (rituximab with pulse CPA versus IV pulse CPA (RITUXVAS 2010) and rituximab alone against oral CPA (RAVE 2010)), and remission definitions. The patient populations differed in that all patients in RITUXVAS 2010 had kidney involvement as opposed to 52% in RAVE 2010. In a subgroup analysis of these patients in RAVE 2010, 61% of the rituximab group and 63% of the CPA group reached the primary endpoint. This does not account for the difference in remission rates between the studies. In RITUXVAS 2010, rituximab was given in conjunction with IV pulses of CPA whereas RAVE 2010 gave rituximab without concomitant CPA. CPA was given orally at 2 mg/kg/day in RAVE 2010 as opposed to the IV pulses in RITUXVAS 2010. There are no data to support a higher remission rate from pulse therapy per se. RITUXVAS 2010 defined remission as a BVAS of 0 for at least two months whereas RAVE 2010 defined remission as a BVAS of 0 and either no steroid treatment or less than 10 mg/day prednisolone. The latter figures from RAVE 2010 are included in this review. The inclusion of steroid doses in the definition of remission may be one of the main influences reducing the apparent remission rate in RAVE 2010.

Mycophenolate mofetil for remission induction

The data currently available on this question have improved markedly with the publication of the initial results of MYCYC 2012. The data now suggests that MMF is an equivalent induction agent to CPA. The next question is the subsequent relapse rate and this has not so far been addressed. If the relapse rate is particularly high, MMF may simply turn out to be an expensive prelude to subsequent CPA. Data from MYCYC 2012 will be available later on the relapse rate in their population.

The populations of patients studied in Han 2011b and Hu 2008b are significantly different from those in other studies, most obviously in the proportion of patients with MPO‐ANCA and MPA at 87%. This is significantly different from that reported from Europe where the majority of patients are PR3‐ANCA positive. The remission rate is also lower than that achieved in similar studies from Europe with only 44% of patients achieving remission (CYCAZAREM 2003) as opposed to over 90% in MYCYC 2012. The external validity of these studies and wider applicability of their results have improved with MYCYC 2012 data showing very similar findings in terms of the comparison with CPA. The predominantly European cohort has again shown a higher level of remission induction on both agents.

Han 2011b is very similar to Hu 2008b. A very similar population of patients diagnosed with MPA were randomised who were almost exclusively MPO‐ANCA positive. Hu 2008b excluded patients with severe and dialysis‐dependent kidney failure whereas Han 2011b did not, though there were only nine patients in this subgroup. Both studies treated with CPA for six months regardless of time to remission and outcomes quoted are at six months only. MYCYC 2012 treated to remission with a minimum of three months CPA and a maximum of six.

Methotrexate for remission induction

The single study (NORAM 2005) comparing the use of oral MTX with oral CPA showed that in patients with early disease and SCr < 150 µM, MTX is an effective induction agent. Time to remission may be a little longer with MTX though this was not conclusively shown. Side effects were similar on the two agents. The relapse rate in this study was high and the MTX group had a significantly higher rate than the CPA group. These data have been used to argue that 12 months of treatment is probably not adequate for patients with these diseases, especially for those with GPA who have a greater tendency to relapse. Considering the data on the utility of MTX as a maintenance agent, this study shows that MTX is a useful induction agent for patients with early systemic vasculitis. Longer term follow‐up of these patients showed that those treated with MTX had longer periods of treatment with other agents than those initially treated with CPA.

Avacopan versus prednisolone for remission induction

A single study (CLEAR 2013) comparing avacopan with prednisolone reported a higher mean eGFR (mL/min/1.73 m²) at three months with avacopan, but no differences between the two treatments for remission. It is currently not clear how a complement inhibitor might fit into a treatment strategy for vasculitis or what the costs and benefits of such a treatment might be.

Intravenous immunoglobulin use for refractory vasculitis

The single study in this area suggests a short‐term benefit lasting no more than three months (Jayne 2000). The treatment can be viewed as a therapy available to help induce remission but has little bearing on the longer term problem of remission maintenance.

Lymphocytapheresis and immunoadsorption

Lymphocytapheresis, described by Furuta 1998, gives some benefit when compared with three weeks of IV pulse methylprednisolone with a significantly lower SCr in treated patients. There was however no change in either the need for dialysis treatment or death at six months. Considering the lack of a comparison with plasma exchange and the recent data suggesting the use of plasma exchange is superior to pulse methylprednisolone, there is currently no compelling reason to consider using this therapy in these conditions. Immunoadsorption, similarly, appears to have no benefit over the use of plasma exchange.

Duration (6 versus 12) of cyclophosphamide induction for remission induction

Two studies compared six pulses with 12 pulses of CPA and no significant differences were found between the two treatments in measuring death, remission, relapse, or infections (CORTAGE 2015; Guillevin 2003). CORTAGE 2015 reported less severe adverse events in patients receiving six pulses.

The numbers used in this review include only MPA patients whereas the original paper also included PAN. The relapse rate was high in the PAN patients treated with six pulses and this gave a significant result on survival analysis. Including all patients in our analysis still did not quite reach statistical significance. This study does not reflect current practice and has in some ways been superseded by CYCAZAREM 2003 which compared a short to a long course of CPA but also included maintenance therapy in the form of AZA. With the inclusion of patients with PAN, the absence of maintenance therapy and its inadequate size, this study is rather difficult to interpret.

Reduced dose versus standard dose steroids for remission induction

PEXIVAS 2013 compared two different doses of steroid and found no differences between the two treatments in terms of remission induction, but did show a reduction in infections with the lower dose steroids. The lower dose of steroids therefore appears to be effective and safer.

Etanercept for remission induction

The stated aim of the single study into the use of etanercept in systemic vasculitis was to demonstrate that the relapse rate would be reduced (WGET 2002). The study failed to show this and also suggested an increase in the incidence of malignancy in treated patients. There are currently no RCT data on the use of infliximab or other anti‐TNF agents. There is some possibility that alternative agents may produce significantly different outcomes since their mechanism of action is distinct from that of etanercept. At this point in time there is no RCT data supporting their use.

Maintenance therapy

Azathioprine versus cyclophosphamide for maintenance therapy

The use of AZA as maintenance therapy after an initial three month treatment with CPA is strongly supported by the data from CYCAZAREM 2003. The number of relapses on AZA is similar to CPA with fewer episodes of leukopenia and similar numbers of infections. As well as the data on reduced leukopenia, the reduction in total dose of CPA is presumed to reduce longer term side effects from CPA such as infertility and neoplasia.

Azathioprine versus mycophenolate mofetil for maintenance therapy

IMPROVE 2003 was designed to test the hypothesis that MMF would be superior to AZA in remission maintenance but showed the opposite with an increased risk of relapse with MMF. Interestingly the separation of the groups started within the first 12 months of maintenance therapy when patients were treated at full dose of MMF. Major relapses appeared after the first year and could perhaps be due to a reduction in therapy. The study is clear, however, in rejecting MMF as a superior alternative to AZA for maintenance therapy.

Azathioprine versus methotrexate for maintenance therapy

WEGENT 2008 showed that the safety and efficacy profiles of MTX and AZA are comparable. The dosing regimen for MTX in this study was superior to that in the leflunomide/MTX study since the rate of rise in dose was faster and the final dose higher (Metzler 2007).

Rituximab versus azathioprine for maintenance therapy

MAINRITSAN 2014 found less major relapses when comparing rituximab to azathioprine, at one and two years and 28 months. There are, however some concerns with the data from this study. As mentioned above, this is one of the first studies where on pulse CPA was used for induction treatment, rather than a mix of oral and pulse CPA and rituximab. The relapse rate was high for the study with the relapse rate achieved with rituximab equivalent to that achieved with AZA in the IMPROVE study. The second problem is that the majority of relapses in this study were major relapses. This has not been reported previously. Whilst rituximab is clearly a superior agent compared to AZA, the final relapse rate achieved is a function of both the induction and maintenance regimens. The relapse rate achieved in the MAINRITSAN study is no better than that achieved previously with different induction regimens.

Co‐trimoxazole (antibiotics) versus placebo for maintenance of remission

The use of co‐trimoxazole to maintain remission was examined by Stegeman 1996. This study showed a benefit in reducing the risk of relapse but not on other outcomes. Analysis in the paper by life table analysis showed this result to be statistically significant. Our analysis found no difference (P = 0.12). Relapses detected in the study were mainly respiratory in nature but 11/23 patients with a relapse also had progressive glomerulonephritis. Zycinska 2009 adds some data to this but still does not clearly answer the question. There were some major limitations in the reporting of this study. Patients were said to be in remission at randomisation but the mean BVAS of the placebo group was 11 (remission is 0). There was no reporting of relapse, only numbers of patients in remission. A firm conclusion is not possible on the available data.

Cyclosporin versus cyclophosphamide for maintenance therapy

The limited data available suggest that there may be a higher relapse rate with the use of cyclosporin. The single trial was small. It is not possible to be conclusive.

Extended versus standard length Azathioprine maintenance therapy

The data strongly support continuation of immunosuppressive treatment with Azathioprine out to approximately 4 years from diagnosis. The REMAIN study was conducted in patients at fairly low risk of relapse. All patients had gone into remission with induction treatment and had no relapses by 18 months post diagnosis. When treatment was tapered, the relapse rate was high over the subsequent two years. This would suggest that patients are safer to continue immunosuppression for at least 4 years after diagnosis and possibly longer for patients at higher risk of relapse.

Leflunomide versus methotrexate for maintenance therapy

The single study of leflunomide suggests that this may be an appropriate treatment for patients who are intolerant of AZA (Metzler 2007). There are problems with interpretation and the external validity of this study. The dose of MTX was increased very slowly. Many commentators felt this to be an inadequate dose, potentially causing the higher relapse rate and inadequately reflecting the potential of MTX in this area. There were also a high number of adverse events in the leflunomide arm. The study does however give some data on the use of leflunomide and grounds for its clinical use. Final conclusions are difficult to draw. Further study of leflunomide is warranted as induction therapy and in comparison to AZA as maintenance therapy

Methotrexate versus cyclophosphamide for maintenance therapy

In a single study, no differences were found when comparing methotrexate with cyclophosphamide for the outcomes of death or relapse.

Tailored versus fixed rituximab for maintenance therapy

A single study compared a tailored schedule of 500mg rituximab infusion with a fixed schedule of 500mg rituximab infusion and reported no differences between treatment groups for death, major relapse, or serious infection at 18 months, but did find severe adverse events to be higher in the fixed schedule group. It is not easy to make clear conclusions from this study. The event rate was low, so the study was under‐powered. There were numerically more relapses (both total and major) in the tailored therapy arm. Also 25% more of the patients were left ANCA positive at the end of treatment compared to the fixed schedule infusion group

Pre‐emptive therapy for relapse

Two studies showed that patients will relapse less often on low level immunosuppression with either AZA or CPA plus prednisolone rather than no change in their treatment (Boomsma 2003; Tervaert 1990). It is difficult to interpret anything else from these studies. At the time they were undertaken, there was some suggestion that an asymptomatic rise in ANCA titre was likely to be a good predictor of imminent relapse. Current literature does not support that hypothesis. Boomsma 2003 was published as an abstract only. It would be interesting to know how many of the patients without an asymptomatic rise had a subsequent relapse. The abstract notes that after immunosuppression, patients went on to have relapses. Those treated did not appear to benefit from a long term protection from relapse.

Belimumab versus placebo for maintenance therapy

BREVAS 2019 compared belimumab to placebo and reported no difference to relapse, any adverse event, or infection. There is currently no evidence for the use of belimumab in the treatment of vasculitis

Overall completeness and applicability of evidence

The data on the treatment of vasculitis remain incomplete. However, this review summarises a significant body of research that represents some high quality data which clearly goes some way to giving guidance on treatment. The areas of the review with data from multiple studies are probably the most helpful and applicable. In these areas, the earlier studies carried multiple problems in disease ascertainment and methodology but their overall conclusions have generally been borne out by the later larger studies. This is reassuring on applicability. In some areas there are many further questions over how to deploy expensive and potentially harmful treatments. One example here is the data on the use of plasma exchange. This review suggests that it is a highly effective therapy when deployed in a particular group of patients, however this result rests on a relatively small number of outcomes. Questions remain as to whether it is a true effect and which patient groups will benefit. The PEXIVAS study should go some way to clarifying this. Data released so far are analyses over the whole seven‐year course of the study and suggest that plasma exchange is not effective in the long term for reducing either death or dialysis. However, the published survival analyses suggest there may well be some effect within the first year on both death and the need for dialysis treatment. The majority of the data in this review is in patients with very poor kidney function. It may also work for patients with good kidney function. This hypothesis is still to be tested. For each of the areas of this review there are multiple such questions still to be answered.

Quality of the evidence

The strength of this review rests on the breadth of the literature search which included non‐English language studies. Unpublished individual patient data were obtained from Adu 1997. This is the first systematic review to cover all areas of renal vasculitis. The review is limited by the small number of available studies answering particular questions and some design features of the included studies. Several older studies included diagnoses other than renal vasculitis. Some date prior to the development of the ANCA assay. This will limit the validity of the data and diagnoses included in those studies. Other differences include those between interventions, notably the regimens of immunosuppressive drugs and the number and volume of plasma exchanges utilised. As noted above, some maintenance treatment studies appear to be influenced by the induction regimen dictated by the protocol, making relapse rates difficult to compare across studies. Some of these issues may have had a very significant impact on the outcomes of studies and may explain the level of heterogeneity in some of the results. Studies of renal vasculitis are notoriously difficult to carry out due to the low incidence of the disease and consequent need for broad collaboration to attain patient numbers for adequately powered studies.

The earlier studies included in this review suffered from some significant methodological problems and inclusion of a wide range of diagnoses which may not have been well validated. The more recent data are of much higher quality. These have generated a significant body of high quality data.

Potential biases in the review process

We have attempted to avoid bias in our review process, including all studies that are available in the area. They have been examined with standard processes. For each update, we have followed our methods from the original protocol, or used revised methods as recommended by Cochrane (e.g. Risk of Bias and GRADE assessment).

Agreements and disagreements with other studies or reviews

Three previous reviews have covered some of the subjects addressed in this review.

Bosch 2007 provides a broad review of the treatment of ANCA‐associated vasculitis. This includes patients with localized disease and those without renal vasculitis. They include a large number of uncontrolled studies and there was no attempt at meta‐analysis. In the area of severe vasculitis with kidney involvement, there is a brief summary of the RCT data as included in this review. Their conclusions are similar to ours.

de Groot 2001 is a review of the data relating to the use of pulse or continuous CPA for induction of remission of ANCA‐associated vasculitis and includes a meta‐analysis of the RCT data. As such, it performs a similar meta‐analysis to ours in this area. There are, however, a number of differences. de Groot 2001 has utilised all the data from Adu 1997. We have extracted the data only for patients without PAN and with some evidence of glomerular involvement. This accounts for some of the differences but not all. de Groot 2001 reports that treatment failure is more likely with continuous treatment with CPA. This is based on 8/25 patients, in Adu 1997, failing treatment. Adu 1997 reports 4/30 patients failed remission induction. Of those, 1/20 suffered treatment failure in the data we have extracted. de Groot 2001 quotes 4/25 patients failing treatment on continuous treatment in Haubitz 1998. Our understanding of this paper suggests that of those four patients, three had in fact died, mostly of sepsis. This is not entirely clear from the paper and we have been so far unable to substantiate this further. Each of these changes contributes to the overall effect in de Groot 2001 showing an increased risk of treatment failure on continuous treatment. Currently we do not believe that a close inspection of the data bears this out. The difference in figures here is also reflected in the results for relapse rate. Our results show that continuous treatment is significantly better at preventing relapse. We have studied relapse as related to the initial number of patients whereas de Groot 2001 have recorded relapses as related to achieved remissions. With the higher treatment failure figures in the continuous arm, de Groot 2001 does not show a significant difference in the overall relapse rate.

Walsh 2011 performed a similar systematic review to ours in the area of plasma exchange and its effect on ESKD, death and a combined endpoint of both. They demonstrated similar results to ours with a profound reduction in the development of ESKD and no effect on death. They then combined those two endpoints to argue that there was little conclusive evidence for the overall effect of plasma exchange on the "hard" endpoint of ESKD and death combined. It is currently our view that combining two outcomes with markedly different results does not serve to appropriately highlight the efficacy of plasma exchange. The current data suggests a striking reduction in the numbers of patients requiring KRT with no change in the risk of death.

Figure 1

Study flow diagram

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Figure 2

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

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Analysis 1.1

Comparison 1 Plasma exchange as adjunctive therapy, Outcome 1 Death.

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Analysis 1.2

Comparison 1 Plasma exchange as adjunctive therapy, Outcome 2 Kidney function: serum creatinine.

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Analysis 1.3

Comparison 1 Plasma exchange as adjunctive therapy, Outcome 3 Dialysis.

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Analysis 1.4

Comparison 1 Plasma exchange as adjunctive therapy, Outcome 4 Sustained remission.

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Analysis 1.5

Comparison 1 Plasma exchange as adjunctive therapy, Outcome 5 Adverse events.

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Analysis 2.1

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 1 Death.

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Analysis 2.2

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 2 Kidney function: serum creatinine.

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Analysis 2.3

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 3 Dialysis.

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Analysis 2.4

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 4 Remission.

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Analysis 2.5

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 5 Relapse.

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Analysis 2.6

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 6 Treatment failure.

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Analysis 2.7

Comparison 2 Pulse versus continuous cyclophosphamide, Outcome 7 Adverse events.

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Analysis 3.1

Comparison 3 Rituximab versus cyclophosphamide, Outcome 1 Death.

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Analysis 3.2

Comparison 3 Rituximab versus cyclophosphamide, Outcome 2 Remission.

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Analysis 3.3

Comparison 3 Rituximab versus cyclophosphamide, Outcome 3 Relapse.

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Analysis 3.4

Comparison 3 Rituximab versus cyclophosphamide, Outcome 4 Adverse events.

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Analysis 3.5

Comparison 3 Rituximab versus cyclophosphamide, Outcome 5 Adverse events (episodes/patient‐months).

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Analysis 4.1

Comparison 4 Mycophenolate mofetil versus cyclophosphamide, Outcome 1 Death.

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Analysis 4.2

Comparison 4 Mycophenolate mofetil versus cyclophosphamide, Outcome 2 Dialysis.

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Analysis 4.3

Comparison 4 Mycophenolate mofetil versus cyclophosphamide, Outcome 3 Remission.

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Analysis 4.4

Comparison 4 Mycophenolate mofetil versus cyclophosphamide, Outcome 4 Relapse.

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Analysis 4.5

Comparison 4 Mycophenolate mofetil versus cyclophosphamide, Outcome 5 Adverse events.

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Analysis 5.1

Comparison 5 Methotrexate versus cyclophosphamide, Outcome 1 Death.

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Analysis 5.2

Comparison 5 Methotrexate versus cyclophosphamide, Outcome 2 Remission.

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Analysis 5.3

Comparison 5 Methotrexate versus cyclophosphamide, Outcome 3 Relapse.

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Analysis 6.1

Comparison 6 Avacopan versus prednisolone, Outcome 1 Death.

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Comparison 6 Avacopan versus prednisolone, Outcome 2 Kidney function: eGFR [mL/min/1.73 m2].

Analysis 6.2

Comparison 6 Avacopan versus prednisolone, Outcome 2 Kidney function: eGFR [mL/min/1.73 m²].

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Analysis 6.3

Comparison 6 Avacopan versus prednisolone, Outcome 3 Remission.

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Analysis 6.4

Comparison 6 Avacopan versus prednisolone, Outcome 4 Relapse.

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Analysis 6.5

Comparison 6 Avacopan versus prednisolone, Outcome 5 Adverse events.

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Analysis 7.1

Comparison 7 Intravenous immunoglobulin versus placebo, Outcome 1 Death.

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Analysis 7.2

Comparison 7 Intravenous immunoglobulin versus placebo, Outcome 2 Response.

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Analysis 7.3

Comparison 7 Intravenous immunoglobulin versus placebo, Outcome 3 Relapse.

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Analysis 7.4

Comparison 7 Intravenous immunoglobulin versus placebo, Outcome 4 Adverse events.

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Analysis 8.1

Comparison 8 Plasma exchange versus immunoadsorption, Outcome 1 Death.

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Analysis 8.2

Comparison 8 Plasma exchange versus immunoadsorption, Outcome 2 Kidney function: serum creatinine.

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Analysis 8.3

Comparison 8 Plasma exchange versus immunoadsorption, Outcome 3 Dialysis.

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Analysis 9.1

Comparison 9 Lymphocytapheresis versus control, Outcome 1 Death.

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Analysis 9.2

Comparison 9 Lymphocytapheresis versus control, Outcome 2 Kidney function: serum creatinine.

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Analysis 9.3

Comparison 9 Lymphocytapheresis versus control, Outcome 3 Dialysis.

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Analysis 10.1

Comparison 10 Six versus 12 cyclophosphamide pulses, Outcome 1 Death.

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Analysis 10.2

Comparison 10 Six versus 12 cyclophosphamide pulses, Outcome 2 Remission.

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Analysis 10.3

Comparison 10 Six versus 12 cyclophosphamide pulses, Outcome 3 Relapse.

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Analysis 10.4

Comparison 10 Six versus 12 cyclophosphamide pulses, Outcome 4 Adverse events.

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Analysis 11.1

Comparison 11 Reduced dose versus standard dose steroids, Outcome 1 Death.

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Analysis 11.2

Comparison 11 Reduced dose versus standard dose steroids, Outcome 2 Dialysis.

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Analysis 11.3

Comparison 11 Reduced dose versus standard dose steroids, Outcome 3 Sustained remission.

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Analysis 11.4

Comparison 11 Reduced dose versus standard dose steroids, Outcome 4 Adverse events.

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Analysis 12.1

Comparison 12 Etanercept versus placebo, Outcome 1 Death.

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Analysis 12.2

Comparison 12 Etanercept versus placebo, Outcome 2 Sustained remission.

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Analysis 12.3

Comparison 12 Etanercept versus placebo, Outcome 3 Relapse.

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Analysis 12.4

Comparison 12 Etanercept versus placebo, Outcome 4 Adverse events.

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Analysis 13.1

Comparison 13 Maintenance therapy: azathioprine versus cyclophosphamide, Outcome 1 Death.

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Analysis 13.2

Comparison 13 Maintenance therapy: azathioprine versus cyclophosphamide, Outcome 2 Dialysis.

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Analysis 13.3

Comparison 13 Maintenance therapy: azathioprine versus cyclophosphamide, Outcome 3 Relapse.

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Analysis 13.4

Comparison 13 Maintenance therapy: azathioprine versus cyclophosphamide, Outcome 4 Adverse events.

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Analysis 13.5

Comparison 13 Maintenance therapy: azathioprine versus cyclophosphamide, Outcome 5 Adverse events (episodes/patient‐months).

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Analysis 14.1

Comparison 14 Maintenance therapy: mycophenolate mofetil versus azathioprine, Outcome 1 Death.

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Analysis 14.2

Comparison 14 Maintenance therapy: mycophenolate mofetil versus azathioprine, Outcome 2 Relapse.

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Analysis 14.3

Comparison 14 Maintenance therapy: mycophenolate mofetil versus azathioprine, Outcome 3 Adverse events.

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Analysis 15.1

Comparison 15 Maintenance therapy: azathioprine versus methotrexate, Outcome 1 Death.

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Analysis 15.2

Comparison 15 Maintenance therapy: azathioprine versus methotrexate, Outcome 2 Relapse.

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Analysis 15.3

Comparison 15 Maintenance therapy: azathioprine versus methotrexate, Outcome 3 Relapse‐free survival.

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Analysis 15.4

Comparison 15 Maintenance therapy: azathioprine versus methotrexate, Outcome 4 Event‐free survival at 24 months.

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Analysis 15.5

Comparison 15 Maintenance therapy: azathioprine versus methotrexate, Outcome 5 Adverse events.

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Analysis 16.1

Comparison 16 Maintenance therapy: rituximab versus azathioprine, Outcome 1 Death.

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Analysis 16.2

Comparison 16 Maintenance therapy: rituximab versus azathioprine, Outcome 2 Major relapse.

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Analysis 16.3

Comparison 16 Maintenance therapy: rituximab versus azathioprine, Outcome 3 Minor relapse.

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Analysis 16.4

Comparison 16 Maintenance therapy: rituximab versus azathioprine, Outcome 4 Adverse events.

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Analysis 17.1

Comparison 17 Maintenance therapy: co‐trimoxazole (antibiotics) versus placebo, Outcome 1 Death.

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Analysis 17.2

Comparison 17 Maintenance therapy: co‐trimoxazole (antibiotics) versus placebo, Outcome 2 Remission.

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Analysis 17.3

Comparison 17 Maintenance therapy: co‐trimoxazole (antibiotics) versus placebo, Outcome 3 Adverse events.

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Analysis 18.1

Comparison 18 Maintenance therapy: cyclosporin versus cyclophosphamide, Outcome 1 Relapse.

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Analysis 19.1

Comparison 19 Maintenance therapy: extended versus standard azathioprine, Outcome 1 Death.

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Analysis 19.2

Comparison 19 Maintenance therapy: extended versus standard azathioprine, Outcome 2 Dialysis.

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Analysis 19.3

Comparison 19 Maintenance therapy: extended versus standard azathioprine, Outcome 3 Relapse.

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Analysis 19.4

Comparison 19 Maintenance therapy: extended versus standard azathioprine, Outcome 4 Adverse events.

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Analysis 19.5

Comparison 19 Maintenance therapy: extended versus standard azathioprine, Outcome 5 Total side effects (episodes/patient‐months).

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Analysis 20.1

Comparison 20 Maintenance therapy: leflunomide versus methotrexate, Outcome 1 Relapse.

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Analysis 20.2

Comparison 20 Maintenance therapy: leflunomide versus methotrexate, Outcome 2 Adverse events.

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Analysis 21.1

Comparison 21 Maintenance therapy: methotrexate versus cyclophosphamide, Outcome 1 Death.

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Analysis 21.2

Comparison 21 Maintenance therapy: methotrexate versus cyclophosphamide, Outcome 2 Relapse.

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Analysis 21.3

Comparison 21 Maintenance therapy: methotrexate versus cyclophosphamide, Outcome 3 Adverse events.

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Analysis 22.1

Comparison 22 Maintenance therapy: tailored versus fixed rituximab, Outcome 1 Death.

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Analysis 22.2

Comparison 22 Maintenance therapy: tailored versus fixed rituximab, Outcome 2 Relapse.

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Analysis 22.3

Comparison 22 Maintenance therapy: tailored versus fixed rituximab, Outcome 3 Adverse events.

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Analysis 23.1

Comparison 23 Maintenance therapy: pre‐emptive therapy for relapse, Outcome 1 Relapse.

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Analysis 24.1

Comparison 24 Maintenance therapy: belimumab versus placebo, Outcome 1 Relapse.

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Analysis 24.2

Comparison 24 Maintenance therapy: belimumab versus placebo, Outcome 2 Adverse events.

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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.
¹ Though some of the studies are of high quality, others have very significant problems (e.g. Mauri 1985; Pusey 1991) ² Event rate and sample size are small 3 High heterogeneity across groups

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

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

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.
¹ Two of these studies had a high risk of bias. ² Sample size and/or event rate were low. ³ Wide 95% CI ⁴ Very different event rates across studies

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

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

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.
¹ Number of events overall is low ² One small study ³ Different event rates in the 2 studies

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

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

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.
¹ Single study results ² Wide CI ³ Some inconsistency in results between studies

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

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

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.
¹ Small sample size; single study results ² Wide CI

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

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Summary of findings 6. Azathioprine versus cyclophosphamide for maintenance therapy

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.
¹ Single study results ² Wide CI

Summary of findings 6. Azathioprine versus cyclophosphamide for maintenance therapy

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Summary of findings 7. Azathioprine versus methotrexate for maintenance therapy

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.
¹ Single study results ² Wide CI

Summary of findings 7. Azathioprine versus methotrexate for maintenance therapy

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Summary of findings 8. Antibiotics versus placebo for maintenance therapy

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.
¹Downgrade 2 levels for study size and limitations with risk of bias assessment ² One study had multiple limitations in the reporting of the study design ³ Two small studies

Summary of findings 8. Antibiotics versus placebo for maintenance therapy

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Summary of findings 9. Leflunomide versus methotrexate for maintenance therapy

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.
¹Downgrade 2 levels for study size and limitations with risk of bias assessment * Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group

Summary of findings 9. Leflunomide versus methotrexate for maintenance therapy

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Comparison 1. Plasma exchange as adjunctive therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5 Adverse events Show forest plot	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]

Comparison 1. Plasma exchange as adjunctive therapy

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Comparison 2. Pulse versus continuous cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Three months	2	181	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.10, 4.73]
1.2 Six months	2	181	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.22, 1.69]
1.3 One year	3	231	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.34, 1.31]
1.4 Two years	3	129	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.21, 2.61]
1.5 Death at final follow‐up	4	278	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.44, 1.32]
2 Kidney function: serum creatinine Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 One month	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Two months	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Three months	1	28	Mean Difference (IV, Random, 95% CI)	‐4.58 [‐97.77, 88.61]
2.4 Six months	1	27	Mean Difference (IV, Random, 95% CI)	51.69 [‐81.03, 184.41]
2.5 Twelve months	2	52	Mean Difference (IV, Random, 95% CI)	‐9.78 [‐53.16, 33.61]
2.6 Two years	2	51	Mean Difference (IV, Random, 95% CI)	4.46 [‐67.90, 76.82]
3 Dialysis Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Three months	1	137	Risk Ratio (M‐H, Random, 95% CI)	2.71 [0.11, 65.43]
3.2 Six months	2	176	Risk Ratio (M‐H, Random, 95% CI)	7.02 [0.90, 54.80]
3.3 Twelve months	1	117	Risk Ratio (M‐H, Random, 95% CI)	3.55 [0.41, 30.80]
3.4 Dialysis end of study	4	245	Risk Ratio (M‐H, Random, 95% CI)	1.90 [0.92, 3.91]
4 Remission Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Three months	1	137	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.81, 1.30]
4.2 Six months	2	176	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.93, 1.13]
4.3 Nine months	1	121	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.92, 1.02]
4.4 Twelve months	1	117	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.94, 1.03]
4.5 Eighteen months	1	116	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.94, 1.03]
4.6 Untimed	1	47	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.98, 1.42]
5 Relapse Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 One year	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.57, 3.69]
5.2 Two years	1	47	Risk Ratio (M‐H, Random, 95% CI)	1.89 [0.51, 7.03]
5.3 Untimed	4	235	Risk Ratio (M‐H, Random, 95% CI)	1.79 [1.11, 2.87]
6 Treatment failure Show forest plot	2	82	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.15, 12.56]

7 Adverse events Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Serious infections	4	278	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.38, 1.33]
7.2 Leukopenia	4	278	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.36, 0.77]
7.3 Nausea	2	97	Risk Ratio (M‐H, Random, 95% CI)	2.51 [1.07, 5.89]

Comparison 2. Pulse versus continuous cyclophosphamide

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Comparison 3. Rituximab versus cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Six months	2	241	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.21, 4.70]
1.2 Two years	1	44	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.24, 4.25]
2 Remission Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Sustained remission at 12 months (censored for death)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Any remission at 12 months (uncensored)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Twelve months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Serious adverse events	2	241	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.72, 1.71]
4.2 Serious infections	2	241	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.42, 1.92]
5 Adverse events (episodes/patient‐months) Show forest plot	2	1710	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.62, 1.32]

Comparison 3. Rituximab versus cyclophosphamide

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Comparison 4. Mycophenolate mofetil versus cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Dialysis Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Remission Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Six months	3	216	Risk Ratio (M‐H, Random, 95% CI)	1.17 [1.01, 1.35]
3.2 Any time point	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.89, 1.09]
4 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 18 months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 At any time point	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Minor relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.4 Major relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Adverse events Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Infections	3	216	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.75, 2.16]
5.2 GI symptoms	2	76	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.17, 1.59]
5.3 Leukopenia	2	76	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.09, 5.15]
5.4 Serious adverse events	1	140	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.86, 1.81]

Comparison 4. Mycophenolate mofetil versus cyclophosphamide

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Comparison 5. Methotrexate versus cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Eighteen months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Remission Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Untimed	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Methotrexate versus cyclophosphamide

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Comparison 6. Avacopan versus prednisolone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Kidney function: eGFR [mL/min/1.73 m²] Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

3 Remission Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Any adverse event	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Serious infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Serious adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 6. Avacopan versus prednisolone

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Comparison 7. Intravenous immunoglobulin versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Response Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Three months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Three months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 7. Intravenous immunoglobulin versus placebo

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Comparison 8. Plasma exchange versus immunoadsorption

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Three months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Kidney function: serum creatinine Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

2.1 Three months	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Six months	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Dialysis Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Three months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 8. Plasma exchange versus immunoadsorption

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Comparison 9. Lymphocytapheresis versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Kidney function: serum creatinine Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

2.1 One month	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Dialysis Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 9. Lymphocytapheresis versus control

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Comparison 10. Six versus 12 cyclophosphamide pulses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 One year	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Three years	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.4 Untimed	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Remission Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Untimed	2	151	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.85, 1.15]
3 Relapse Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Untimed	2	133	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.96, 2.56]
4 Adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Infection	2	169	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.36, 1.72]
4.2 Severe adverse events	1	104	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.59, 1.00]
4.3 Cytopenia	1	104	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.10, 1.28]

Comparison 10. Six versus 12 cyclophosphamide pulses

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Comparison 11. Reduced dose versus standard dose steroids

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Dialysis Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Sustained remission Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Serious adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Serious infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 11. Reduced dose versus standard dose steroids

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Comparison 12. Etanercept versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Sustained remission Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Cancer	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 12. Etanercept versus placebo

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Comparison 13. Maintenance therapy: azathioprine versus cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Long‐term follow‐up (median time 8.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Dialysis Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Long‐term follow‐up (median time 8.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Eighteen months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Long‐term follow‐up (median time 8.5 years)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Infection	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]
4.3 Serious adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Adverse events (episodes/patient‐months) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Leukopenia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 13. Maintenance therapy: azathioprine versus cyclophosphamide

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Comparison 14. Maintenance therapy: mycophenolate mofetil versus azathioprine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Untimed	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Any relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Major relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Minor relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Any adverse event	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Serious infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Leukopenia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Serious adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 14. Maintenance therapy: mycophenolate mofetil versus azathioprine

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Comparison 15. Maintenance therapy: azathioprine versus methotrexate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Death due to study drug	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Relapse‐free survival Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 18 months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 24 months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 36 months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Event‐free survival at 24 months Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Any adverse event	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Severe adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Adverse event causing death or study drug discontinuation	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 15. Maintenance therapy: azathioprine versus methotrexate

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Comparison 16. Maintenance therapy: rituximab versus azathioprine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Major relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 One year	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Two years	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 End of study (28 months)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Minor relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 One year	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Two years	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 End of study (28 months)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.1 Serious infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 16. Maintenance therapy: rituximab versus azathioprine

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Comparison 17. Maintenance therapy: co‐trimoxazole (antibiotics) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Six months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Remission Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 One year	2	111	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.98, 1.33]
2.2 18 months	1	31	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.81, 2.44]
2.3 Two years	1	80	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.94, 1.76]
3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Anorexia and nausea	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Rash	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Interstitial nephritis	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Asymptomatic hepatotoxic effects	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 Recurrent urinary tract infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.6 Adverse events causing study drug discontinuation	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 17. Maintenance therapy: co‐trimoxazole (antibiotics) versus placebo

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Comparison 18. Maintenance therapy: cyclosporin versus cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 18. Maintenance therapy: cyclosporin versus cyclophosphamide

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Comparison 19. Maintenance therapy: extended versus standard azathioprine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	2	162	Risk Difference (M‐H, Random, 95% CI)	0.06 [‐0.01, 0.13]

2 Dialysis Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Relapse Show forest plot	2	162	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.26, 0.64]

4 Adverse events Show forest plot	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) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 19. Maintenance therapy: extended versus standard azathioprine

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Comparison 20. Maintenance therapy: leflunomide versus methotrexate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse Show forest plot	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 Show forest plot	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]

Comparison 20. Maintenance therapy: leflunomide versus methotrexate

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Comparison 21. Maintenance therapy: methotrexate versus cyclophosphamide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 All relapses	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Major relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Minor relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Serious infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Leukopenia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 21. Maintenance therapy: methotrexate versus cyclophosphamide

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Comparison 22. Maintenance therapy: tailored versus fixed rituximab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Major relapse	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Severe adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Serious infections	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 22. Maintenance therapy: tailored versus fixed rituximab

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Comparison 23. Maintenance therapy: pre‐emptive therapy for relapse

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse Show forest plot	2	60	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.03, 1.59]

Comparison 23. Maintenance therapy: pre‐emptive therapy for relapse

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Comparison 24. Maintenance therapy: belimumab versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2 Adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Any adverse event	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 24. Maintenance therapy: belimumab versus placebo

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Idioma de la Revisión Cochrane

Idioma de la web

Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

PICO

PICO

Population

Intervention

Comparison

Outcome

Resumen en términos sencillos

Intervenciones para la vasculitis renal en adultos

Resumen visual

Authors' conclusions

Implications for practice

Implications for research

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

Included studies

Types of treatments for remission induction

Types of maintenance therapies

Diagnoses

Excluded studies

Risk of bias in included studies

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Detection bias

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Remission induction studies

1: Plasma exchange as adjunctive therapy

2: Pulse versus continuous cyclophosphamide

3: Rituximab versus cyclophosphamide

4: Mycophenolate mofetil versus cyclophosphamide

5: Methotrexate versus cyclophosphamide

6: Avacopan versus prednisolone

7: Intravenous immunoglobulin use in persistent disease