Objective To summarise and update evidence to inform the 2022 update of the EULAR recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitis (AAV).
Methods A systematic literature review (SLR) was performed to identify current evidence regarding treatment of AAV. PubMed, EMBASE and the Cochrane library were searched from 1 February 2015 to 25 February 2022. The evidence presented here is focused on the treatment of granulomatosis with polyangiitis and microscopic polyangiitis.
Results 3517 articles were screened and 175 assessed by full-text review. Ninety articles were included in the final evidence synthesis. Cyclophosphamide and rituximab (RTX) show similar efficacy for remission induction (level of evidence (LoE) 1a) but RTX is more effective in relapsing disease (LoE 1b). Glucocorticoid (GC) protocols with faster tapering result in similar remission rates but lower rates of serious infections (LoE 1b). Avacopan can be used to rapidly taper and replace GC (LoE 1b). Data on plasma exchange are inconsistent depending on the analysed trial populations but meta-analyses based on randomised controlled trials demonstrate a reduction of the risk of end-stage kidney disease at 1 year but not during long-term follow-up (LoE 1a). Use of RTX for maintenance of remission is associated with lower relapse rates compared with azathioprine (AZA, LoE 1b). Prolonged maintenance treatment results in lower relapse rates for both, AZA (LoE 1b) and RTX (LoE 1b).
Conclusion This SLR provides current evidence to inform the 2022 update of the EULAR recommendations for the management of AAV.
- systemic vasculitis
- granulomatosis with polyangiitis
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Since the publication of the previous EULAR recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis in 2016, several landmark trials have been published and refined treatment strategies in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
WHAT THIS STUDY ADDS
This review highlights new evidence derived from randomised controlled trials and meta-analyses regarding remission induction, glucocorticoid dosing, plasma exchange and maintenance treatment for ANCA-associated vasculitis (AAV).
Cyclophosphamide and rituximab have overall similar efficacy for induction treatment but rituximab shows superior capacity in relapsing patients.
Glucocorticoid-sparing protocols are non-inferior to conventional tapering schemes in terms of efficacy and have lower serious infection rates.
Avacopan can be used to rapidly taper and replace glucocorticoids during induction treatment.
Available data on the effect of plasma exchange are conflicting.
Recent meta-analyses suggest that plasma exchange may lower the risk of end-stage kidney disease at 12 months (but not during long-term follow-up) in renal vasculitis.
The available data demonstrate no efficacy of plasma exchange to reduce mortality.
Use of rituximab for maintenance of remission is associated with lower relapse rates compared with azathioprine.
Prolonged maintenance treatment results in lower relapse rates.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The results of this systematic literature review will shape the treatment approaches for patients with GPA and MPA.
The 2022 update of the EULAR recommendations for the treatment of AAV have been based on this evidence synthesis.
Since the 2016 update of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV),1 several high-impact clinical trials have broadened the repertory of available treatments for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and refined management strategies in daily routine care.2–7
Cyclophosphamide (CYC) and glucocorticoids (GC) have been the mainstay of remission induction treatment in AAV.8 Even though successful strategies to reduce the exposure of CYC and GC, including the use of rituximab (RTX) have been in use for several years now,9 10 the toxicity and sequelae caused by these substances remain an unsolved issue in AAV.11 12 The optimal management and duration of immunosuppressive treatment balancing risk of relapse and risk of treatment-induced complications is an ongoing challenge during long-term follow-up. Biomarkers guiding the intensity or duration of immunosuppression are not yet established. Since the last update, new information is available on (i) the use of mycophenolate mofetil (MMF) for remission induction,5 13 (ii) reduced-dose GC schemes,2 6 (iii) GC-sparing treatment with avacopan,4 (iv) the efficacy of plasma exchange (PLEX),2 (v) dosing and duration of remission maintenance treatment with conventional immunosuppressives and RTX3 7 14 and (vi) pooled evidence from meta-analyses on several areas of the management of AAV.15 16
We conducted a systematic literature review (SLR) focused on treatment of GPA and MPA. The results presented here will provide the available evidence to the task force of the 2022 update of the EULAR recommendations for the management of AAV.17 A second complementary article will cover the treatment of eosinophilic granulomatosis with polyangiitis as well as diagnostic procedures and general management of AAV.18
The SLR was performed according to the EULAR standard operating procedures (SOP) for EULAR-endorsed recommendations.19 A methods protocol was established prior to the conduct of the review. Based on a Delphi survey administered to the whole task force (including field expert physicians, one healthcare professional and two patient representatives), eight research questions in the patient, intervention, comparator, outcome (PICO) format were developed to address treatment of GPA and MPA (online supplemental file 1). An electronic search focusing on treatment of AAV was performed in PubMed, EMBASE and the Cochrane Library databases (including trial registries clinicaltrials.gov and the WHO Clinical Trial Registry platform). Search strings were developed in collaboration with an experienced librarian. The search was performed as an update starting with the end date of the SLR of the previous recommendations (1 February 2015)1 and included studies up to 25 February 2022. For treatments not included in the last recommendations, a search without time restrictions was done. Randomised controlled trials (RCTs) and non-randomised intervention studies were included in the review. Congress abstracts of the international meetings of EULAR, the American College of Rheumatology (ACR), the American Society of Nephrology, the European Renal Association/European Dialysis and Transplant Association and the Vasculitis and ANCA Workshop were additionally screened for abstracts of RCTs. Detailed PICO questions, search strategies and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram are provided in the online supplemental file 1.
The SLR was performed by two independent reviewers (BS-A and JHS) under supervision of two methodologists (RAL, GT). Articles delivered by the electronic database search were screened by review of title and abstract (10% in duplicate with >80% agreement) and relevant articles selected for full-text review. Both reviewers agreed on the included studies by consensus and disagreements were resolved by discussion. Included articles were summarised in piloted summary of evidence tables during full-text review (50% in duplicate). Data and quality of evidence of studies included in the final data synthesis were agreed on by both reviewers. Disagreements were resolved by discussion. In case of uncertainties, methodologists were consulted to resolve open questions. Case reports, editorials, retrospective studies with mixed populations (not mainly consisting of patients with AAV), retrospective studies with <50 patients with GPA/MPA and prospective studies with <10 patients with AAV were excluded. The SLR was limited to articles in English language.
The 2009 Oxford Centre for Evidence-Based Medicine levels of evidence (LoE) were assigned to included studies.20 Risk of bias (RoB) was assessed using the AMSTAR 221 tool for systematic reviews and meta-analyses, RoB 2 for randomised trials,22 ROBINS-I for non-randomised intervention studies23 and the Newcastle-Ottawa Scale for case series or intervention studies without control group (‘self-controlled before-after’).24
The search strategy identified 3517 articles (after deduplication). One hundred and seventy-five articles were selected for full-text review. Details are provided in the online supplemental file 1. Ninety articles2–7 11 13–16 25–103 addressing GPA and MPA treatment were included for evidence synthesis (online supplemental file 2).
Remission induction treatment with immunosuppressives
Three meta-analyses of RCTs were identified that reported pooled estimates from comparing intravenous pulsed and continuous oral CYC.15 16 71 The main results are summarised in table 1. Two meta-analyses15 71 compared remission rates and found them not significantly different between the CYC regimens. Two meta-analyses compared relapse risk between the regimens and found them to be higher in patients treated with intravenous pulsed CYC compared with oral CYC. Risk of leucopenia (a well-defined risk factor for infectious complications) was lower in patients treated with intravenous pulsed CYC.15 16
One new RCT comparing different CYC regimens was identified since the 2016 AAV EULAR recommendations. The CORTAGE trial included a mixed population of necrotising vasculitides (mainly GPA and MPA but also EGPA and polyarteritis nodosa (PAN)) aged ≥65 years and compared an induction regimen with reduced dose and duration and a conventional treatment (table 2).73 The intervention group received GC that were tapered and discontinued at 9 months combined with fixed-dose 500 mg intravenous CYC pulses for induction (given until remission, maximum six pulses), afterwards switched to maintenance treatment with azathioprine (AZA), methotrexate (MTX) or MMF. The conventional treatment (control) group received higher doses of GC that were reduced over a longer period (discontinued by 26 months) combined with CYC, dosed according to body surface area (500 mg/m2) followed by three consolidation pulses, then the same maintenance treatment as in the intervention group. Patients with EGPA or PAN and a 1996 Five-Factor Score of 0 in the control group received only GC. The primary outcome was the occurrence of ≥1 serious adverse event (SAE) over 3 years, which occurred less frequently in the intervention arm compared with the conventional treatment arm. Relapses were not significantly (p=0.15), but numerically more frequent in the reduced-dose arm (20 of 45; 44%) compared with the control arm (12 of 41; 29%).
Supplementary studies from the ‘General Management’ section in the second SLR manuscript report dose-dependent increase of malignancy risk and early menopause under CYC treatment that need to be considered when choosing agents for induction treatment.18
In summary, continuous oral and intravenous pulsed CYC combined with GC show similar efficacy in the induction of remission (LoE 1a). Continuous oral CYC is associated with a lower rate of relapse but a higher rate of leucopenia, a well-known risk factor for serious infections (LoE 1a). Reduced-dose CYC and GC for induction treatment in elderly patients reduces the rate of SAEs (LoE 2b) but that could come at the cost of lower efficacy in preventing relapses.
A Cochrane Review and meta-analysis reported pooled estimates from two RCTs comparing RTX and CYC induction treatment and showed no differences for achieving remission at 6 months (risk ratio (RR 1.02, 95% CI 0.79 to 1.32), relapse at 12 months (RR 1.43, 95% CI 0.18 to 11.31) nor risk of death at 6 months (RR 1.00, 95% CI 0.21 to 4.70). There was no difference in serious infections (RR 0.89, 95% CI 0.62 to 1.92) and SAEs (RR 1.11, 95% CI 0.72 to 1.71) between the treatments.15
No new RCTs comparing RTX with another remission induction treatment were identified since the last update. A post hoc analysis94 of the randomised controlled double-blind RAVE trial9 that compared RTX and CYC for remission induction in AAV, identified subgroups of importance regarding the efficacy of RTX. The main results from the RAVE trial reported overall non-inferiority of remission induction treatment with RTX compared with CYC (+AZA). RTX induction was superior in those patients with relapsing disease at baseline, 6 and 12, but not at 18 months of follow-up.9 104 Furthermore, higher rates of relapse were reported for patients with proteinase 3 (PR3)-ANCA (compared with Myeloperoxidase (MPO)), patients with GPA (compared with MPA) and those with relapsing (compared with new-onset) disease. The post hoc analysis grouped patients by ANCA specificity and diagnoses.94 The odds of being in complete remission at 6 months (but not at 12 or 18 months) were higher in patients with PR3-ANCA (including newly onset and relapsing patients) treated with RTX compared with those treated with CYC/AZA (OR 2.11, 95% CI 1.04 to 4.30). When relapsing patients with PR3-ANCA were analysed, the likelihood of being in remission were higher in those treated with RTX compared with CYC/AZA at 6 months (OR 3.57, 95% CI 1.43 to 8.93), 12 (OR 4.32, 95% CI 1.53 to 12.15) and 18 months (OR 3.06, 95% CI 1.05 to 8.97), even though RTX-treated patients received no additional maintenance treatment in the RAVE trial. No difference for remission rates after RTX or CYC/AZA induction was shown for GPA, MPA, newly diagnosed PR3-AAV or newly diagnosed MPO-AAV. Furthermore, high remission rates (90%) after induction treatment of relapsing AAV with RTX are reported in the induction phase of the RITAZAREM trial (no control group in the induction phase of the trial).85
No RCTs comparing different doses of RTX were identified. A systematic review of available studies, mainly consisting of non-randomised studies including case reports, reported comparable effect sizes of reaching complete remission of 85% (70% to 96%) and 91% (79% to 99%) for induction regimens with RTX 4×375 mg/m2 weekly vs 2×1000 mg biweekly with significant RoB resulting from heterogeneity of included reports.28
In summary, RTX shows similar efficacy for remission induction in AAV compared with CYC (LoE 1a) but RTX leads to longer lasting remission rates compared with CYC in patients with relapsing disease course (LoE 2b). No difference in efficacy of four-infusion and two-infusion protocols of RTX has been shown, yet (LoE 4), but high-quality evidence is lacking.
Combination treatment with rituximab and cyclophosphamide
Only one RCT (RITUXVAS) compared the combination of CYC and RTX with a regimen consisting of intravenous CYC (followed by AZA maintenance) for remission induction treatment in 44 patients with renal AAV.10 54 Rates of remission/relapse, SAEs, infections and deaths were not significantly different between intervention and control group at 1 and 2 years. SAEs (CYC+RTX: 20 of 33, 61%; CYC 4 of 11, 36%) and serious infections (CYC+RTX 11 of 33, 33%; CYC: 2 of 11, 18%) were numerically higher in the CYC+RTX group after 2 years. Some retrospective studies reported high rates of remission, low relapse rates, slow progression towards permanent kidney failure and reduced GC use as compared with earlier published cohorts when combining CYC, RTX and in one cohort also PLEX. Other retrospective studies reported increased rates of neutropenia or infections when CYC and RTX were combined.36 47 62 74 92 103 Due to the lack of a randomised control group, multiple therapeutic interventions and settings, variable individual GC doses, a relevant RoB remains. A randomised trial comparing induction treatment with a combination of RTX and CYC with RTX without CYC is ongoing (NCT03942887).
In summary, available data preclude solid conclusions regarding efficacy and safety of induction treatment with combined RTX and CYC, as compared with induction treatment with either CYC or RTX, yet.
Four meta-analyses pooled results from four RCTs that compared MMF and CYC for remission induction (table 3).29 55 86 99 No differences were reported for rates of remission, relapse, death, infection, nor leucopenia. The meta-analyses included two RCTs comparing MMF and CYC for remission induction that were published since the 2016 EULAR recommendations for AAV (table 2).
The MYCYC trial compared MMF with intravenous pulsed CYC (both combined with GC and followed by AZA maintenance) in new-onset non-severe AAV.5 Remission at 6 months was not different between the intervention and control groups and fulfilled the criteria for non-inferiority. However, relapses were observed more frequently in the MMF group (incidence rate ratio 1.97, 95% CI 0.96 to 4.23), this effect was driven by patients with PR3-positive disease (two RCTs published before the start date of our SLR update included mainly patients with MPA that were MPO-ANCA positive105 106).
Tuin et al compared MMF with continuous oral CYC in relapsing AAV.13 The primary end point was stable remission at month 6 which was reached in 66% in MMF group and 81% in CYC group (numerical difference not reaching statistical significance). No significant difference in relapse was observed.
All four mentioned RCTs excluded patients with imminently life-threatening disease and three of them also excluded patients with most severe renal disease.
In summary, there is evidence that the efficacy of MMF combined with GC to induce remission is similar to CYC combined with GC in GPA and MPA without imminently life-threatening vasculitis (LoE 1a). However, there seem to be higher relapse rates in PR3-ANCA-positive patients treated with MMF compared with CYC.
Induction treatment of organ-threatening or life-threatening versus non-organ-threatening or life-threatening disease
The NORAM trial is usually viewed as the primary example of a trial investigating induction regimens in non-organ-threatening or life-threatening disease.107 No new RCTs were identified since the last update, which investigated treatment agents exclusively in non-organ-threatening or non-life-threatening AAV. However, there is no overarching definition of organ-threatening or life-threatening disease that is uniformly used in clinical trials and several newly identified trials included mixed populations with and without potentially organ-threatening or life-threatening manifestations.5 6 13 85 Increased relapse rates after induction with MTX or MMF (LoE 1b) compared with more potent treatments must be considered when choosing induction treatment.5 107 Adverse drug effects also have to be considered (studies on malignancy risk and infertility associated with CYC are discussed in the second corresponding SLR article).
The open-label ALEVIATE trial reported safety and efficacy of two different doses of alemtuzumab in a cohort with refractory AAV (n=12) or Behçet’s disease (n=11). Nine (75%) and five (41.6%) patients with AAV had complete or partial response at 6 and 12 months, respectively (LoE 4). The search strategy for this SLR identified the data in form of an abstract (the trial has now been fully published).46 108
Overall, data reporting efficacy of treatment for refractory disease is scarce and this situation requires expert consultation and individualised treatment.
Two RCTs compared different GC regimens (table 2). The PEXIVAS trial included patients with severe (defined by active renal involvement and estimated glomerular filtration rate <50 mL/min/1.73 m2 or pulmonary haemorrhage) GPA or MPA and compared a reduced-dose GC regimen to a standard regimen2 (table 4), combined with induction treatment with either CYC or RTX with or without additional PLEX. All patients received intravenous methylprednisolone (MP) pulse treatment for 1–3 days (cumulative maximum dose 3 g), before receiving one of the two oral GC regimens. The reduced-dose GC regimen was non-inferior compared with the standard-dose regimen for the primary composite end point, which was death of any cause or end-stage kidney disease (ESKD). HR for sustained remission was not significantly different for the reduced versus the standard-dose GC regimen (HR 1.04, 95% CI 0.92 to 1.19) but risk of serious infections at 1 year was lower (HR 0.69, 95% CI 0.52 to 0.93).
The LoVAS trial included newly diagnosed patients with GPA, MPA or renal limited vasculitis (RLV).6 All subjects received remission induction treatment with RTX and were randomised to receive either reduced-dose GC or high-dose GC treatment (table 4). Subjects with severe glomerulonephritis (glomerular filtration rate (GFR) <15 mL/min/1.73 m2 or alveolar haemorrhage requiring >2 L oxygen/min) were excluded. MP pulse treatment was not allowed in either group. The trial demonstrated that the reduced-dose regimen is non-inferior compared with the high-dose regimen with regard to remission at 6 months. SAEs and severe infections were significantly less frequent in the reduced-dose compared with the high-dose group.
Both trials had differences in the included populations and the regimens they propose may be convenient for different patient groups: while the PEXIVAS trial included also patients at severe disease stages, the LoVAS trial, that used an even lower GC dosing scheme, excluded patients with most severe renal and pulmonary involvement and the majority of patients in LoVAS were MPO-ANCA positive (which may be a factor associated with lower relapse risk). These trials are the only RCTs identified by a systematic review of studies comparing GC regimens in AAV.98
The non-controlled SCOUT study reported even shorter GC taper over 8 weeks in patients treated with RTX.66 The patients achieved remission rates compatible with controls from the RAVE trial (OR 1.31, 95% CI 0.26 to 6.56) and median adverse events (AEs) per patient were less frequent (2 vs 8, p<0.001) but consecutive relapse rate was higher (30% vs 7%, p=0.03), highlighting the previously described association of prolonged GC treatment with less relapses.109
No RCTs informing about benefits and risks of intravenous GC pulses were identified. A retrospective cohort study suggests that GC pulses may increase the risk of infections and diabetes while showing no difference in survival, renal recovery or relapse.32 One article reported GC pulse treatment to be associated with the ability to stop maintenance treatment,48 while other authors report no significant effect of GC pulse treatment given in patients with AAV on dialysis at disease onset with regard to survival, renal recovery or AEs.49 The SLR for general management reported in the second complementary SLR manuscript included risk factors on infections: GC pulse treatment is reported to be associated with infection by some retrospective studies110–114 identified in the supplementary SLR, while no significant associations (or associations not reaching statistical significance) is reported by others.115–117 Randomised studies are needed to compare efficacy of pulse GC (eg, fast and durable remission in patients with organ-threatening or life-threatening disease) and potential harms in AAV.
In summary, reduced-dose GC regimens reduce the rate of infectious complications while showing similar efficacy to conventional GC regimens when combined with remission induction treatments (LoE 1b for both studied regimens used in different populations). The benefits and risks of GC pulse treatment remain not well defined.
Three RCTs reported on the use of the complement C5 receptor antagonist avacopan for GPA and MPA (table 2). The phase II CLASSIC trial compared 10 mg avacopan twice daily and 30 mg avacopan twice daily with placebo (all groups combined with induction treatment consisting of GC and RTX or CYC), the primary end point was safety. AE and infection rates were similar among groups.64 The phase II CLEAR trial compared efficacy of placebo+prednisone (starting at 60 mg/day), avacopan 30 mg twice daily+prednisone (starting at 20 mg/day) and avacopan+placebo.53 All groups received induction treatment with CYC or RTX. The primary efficacy outcome (response at week 12) was reached by 70% in the control arm, 86.4% in the avacopan+reduced-dose GC arm and 81.0% in the avacopan+placebo arm (non-inferiority for both avacopan arms compared with standard GC). The AE rate was similar between trial arms. The phase III ADVOCATE trial enrolled newly diagnosed or relapsing GPA and MPA to receive either avacopan 30 mg twice daily (with maximum 20 mg prednisone initially, tapered and stopped within 4 weeks) for 52 weeks or a prednisone tapering scheme starting at 60 mg (lower in persons weighing <55 kg) that was tapered and discontinued at week 21. In contrast to the 21-week GC course in the control group, avacopan was continued up to week 52 in the intervention group. Both groups received additional remission induction treatment with RTX or CYC (intravenous or oral), followed by AZA maintenance if CYC was given. Avacopan met the non-inferiority criterion for remission at week 26 and the superiority criterion for remission at week 52. The difference of sustained remission at week 52 between patients randomised to GC or avacopan was low if CYC was used for remission induction (CYC+GC: 52.6%, CYC+avacopan: 55.9%) but pronounced in those that receivedRTX for induction treatment (RTX+GC: 56.1%, RTX+avacopan: 71.0%). However, patients treated with RTX induction did not receive maintenance treatment and GC were given for a shorter period than avacopan in this trial. The lower GC exposure in the avacopan group translated into less GC-related toxicity. Recovery of renal function seemed to be higher in the avacopan-treated group (mean eGFR 7.3 mL/min/1.73 m2), compared with the GC group (mean eGFR 4.1 mL/min/1.73 m2), mean difference between groups 3.2 mL/min/1.73 m2 (95% CI 0.3 to 6.1). This was pronounced in the subgroup of patients with worse renal function (GFR <30 mL/min/1.73 m2), mean difference 5.6 mL/min/1.73 m2 (95% CI 1.7 to 9.5).
In summary, there is good quality evidence that the use of avacopan instead of high-dose GC in CYC-based or RTX-based protocols leads to similar rates of remission and is associated with less GC-related toxicity (LoE 1b).
The PEXIVAS trial (table 2) compared the efficacy of adjunctive PLEX in addition to remission induction (GC and CYC or RTX) in 704 patients with new-onset or relapsing GPA or MPA with active renal involvement or alveolar haemorrhage.2 The primary end point was the composite of death from any cause or ESKD. PEXIVAS found no difference between treatment arms (induction treatment with or without adjunctive PLEX) with respect to neither the primary outcome death of any cause or ESKD nor the secondary outcomes when these were analysed independently. The primary outcome of combined death or ESKD was also not significantly reduced in subgroup analyses for alveolar haemorrhage (in two subgroups with oxygen saturation >85% or ≤85% on room air/invasive ventilation).
Several meta-analyses15 16 27 96 100 101 have addressed the potential benefit of PLEX (table 5). None of the meta-analyses showed a benefit with respect to mortality15 16 27 96 100 101 nor identified a subgroup of patients with AAV for which PLEX decreases the risk of death. Regarding potential benefit of PLEX for preventing ESKD, the meta-analyses provide somewhat conflicting results (table 5): two meta-analyses including RCTs only (but no observational studies) found the risk of ESKD to be reduced at 1 year. The only meta-analysis that included data from the PEXIVAS trial (total seven RCTs) but no non-randomised observational studies in the 12-month analysis found that PLEX decreased the risk of ESKD at 1 year but not at long-term follow-up (median 3 years).96 A lower risk of dialysis dependence at 1 year was also reported in a Cochrane Review by Walters et al that did not include PEXIVAS (total six RCTs). Three meta-analyses that included a low number of subjects100 or included non-randomised observational studies27 101 found that PLEX did not reduce the overall risk of ESKD at 1 year. Two meta-analyses found that benefit of PLEX may be highest in patients at high risk of ESKD.16 96 Walsh et al96 grouped patients according to baseline creatinine as risk factor for subsequent ESKD (low risk ≤200 µmol/L, low to moderate risk >200–300 µmol/L, moderate to high risk >300–500 µmol/L and high risk >500 µmol/L or dialysis dependency) and calculated a risk reduction of 4.6% in the moderate-risk to high-risk group and of 16.0% in the high-risk group. Other studies have investigated subgroups that might be of importance with respect to potential benefit of PLEX.72 However, biomarker-defined subgroups that may be more likely to benefit from PLEX have not been investigated in prospective trials.
Two meta-analyses (those including the largest number of RCTs) found that PLEX increases the risk of severe infections,15 96 whereas four (with overall lower numbers of RCTs included in the analysis or analysis was based on pooled data from RCTs and non-randomised studies) reported no significantly increased infection risk.16 27 100 101
In summary, the results of the most recent and largest trial (PEXIVAS) did not demonstrate a significant reduction of mortality and ESKD in patients with organ-threatening or life-threatening AAV (LoE 1b). Some, but not all, meta-analyses suggest a benefit of PLEX with respect to ESKD at 1 year (but not during long-term follow-up), especially so among those with severely impaired kidney function. This potential benefit of PLEX in AAV must be counterbalanced against the presumably increased risk of severe infections associated with PLEX (LoE 1a). There is no evidence that PLEX improves outcomes related to Diffuse alveolar hemorrhage (LoE 1b).
Remission maintenance treatment
Maintenance treatment with conventional immunosuppressives
A meta-analysis (table 6) pooled results from two RCTs that investigated prolonged remission maintenance treatment with AZA and demonstrated a reduction of relapse risk but not mortality for prolonged AZA maintenance.15 Both included RCTs were also identified by the SLR update: the REMAIN trial3 and the AZA-ANCA trial81 (table 7).
The REMAIN trial randomised GPA, MPA or RLV with a history of renal involvement or other organ-threatening manifestations that were in stable remission under AZA and GC after successful remission induction with CYC.3 The intervention group received continued AZA and GC until 48 months from diagnosis, in the control group AZA and GC were withdrawn by 24 months. Relapses were significantly more common in the withdrawal than in the continued maintenance group. Major relapses were significantly more common in the withdrawal group (35.3%) than in the continued maintenance group (13.5%). The decrease of renal function (compared with initial function) was significantly more distinct in the withdrawal group but not in the prolonged maintenance group (where renal function slightly increased). Four (7.8%) in the withdrawal group but no patients in the prolonged maintenance group developed ESKD (p=0.012). AEs, infections and cytopenias were numerically higher in the continued maintenance group but the difference did not reach statistical significance. However, the trial may be underpowered to detect significant differences for AEs.
The AZA-ANCA trial included patients that achieved remission within 6 months after induction treatment with CYC and GC for newly diagnosed PR3-AAV.81 Those with a C-ANCA titre ≥1:40 (by indirect immunofluorescence) at switch to AZA maintenance (after 3 months of stable remission) were randomised to receive AZA with an ‘extended’ (until 4 years after diagnosis and tapered afterwards) or ‘standard’ (until 1 year after diagnosis with successive tapering by 25 mg every 3 months) duration regimen. Five of 21 patients in the extended group and 11 of 24 patients in the ‘standard’ group relapsed within 4 years. Relapses were numerically more frequent in the ‘standard’ compared with the ‘extended’ group, but the difference did not reach statistical significance. These results have to be interpreted in the context of early closing of trial enrolment.
The POWERCIME trial (table 7) included patients with active (newly diagnosed or relapsing/refractory) AAV (GPA, MPA or EGPA).61 The patients received induction treatment with oral CYC and GC and, after achieving remission, were randomised to receive maintenance treatment with either MTX or continued oral CYC. The primary end point (relapse at month 12 from start of maintenance treatment) did not differ between groups (neither in the whole trial population including EGPA, nor in the subgroup analysis including 41 patients diagnosed with GPA or MPA). The interpretation of results is limited by a premature closure of enrolment.
The SLR retrieved no further new RCTs on the use of MMF or other conventional immunosuppressive agents for remission maintenance. In an earlier RCT (WEGENT), AZA and and MTX showed similar efficacy for remission maintenance treatment.118 The IMPROVE trial showed higher relapse risk for remission maintenance treatment with MMF as compared with AZA (HR 1.69; 95% CI 1.06 to 2.70; p=0.03).119
In summary, prolonged AZA treatment significantly reduces relapse rate (LoE 1a) and seems to be associated with better renal prognosis. AZA and MTX have similar efficacy for remission maintenance treatment (LoE 1b), whereas relapse risk is higher for maintenance treatment with MMF as compared with AZA (LoE 1b).
Maintenance treatment with rituximab
Several RCTs on the use of RTX for remission maintenance have been published since the 2016 EULAR recommendations for AAV.
In the RITAZAREM trial (table 7), patients with relapsing GPA or MPA received remission induction treatment with RTX and GC. Those achieving disease control by month 4 were randomised to receive maintenance treatment with either 1000 mg RTX at months 4, 8, 12, 16 or AZA (and standardised GC tapering). The SLR identified preliminary data (published as abstract only84) but the full publication became recently available.120 The trial results demonstrate relapse risk to be significantly lower in the RTX compared with the AZA group. This supports the findings of the MAINRITSAN trial comparing RTX for 18 months and AZA for 22 months for remission maintenance treatment after induction treatment with CYC and GC. The MAINRITSAN trial reported RTX to be more efficacious than AZA to prevent relapses at 28 months (HR 6.61; 95% CI 1.56 to 27.96; p=0.002).121 Major relapse-free survival remained better in the RTX group (71.9%; 95% CI 61.2% to 84.6%) compared with the AZA group (49.4%; 95% CI 38.0% to 64.3%; p=0.003) at 60 months of follow-up.90
The MAINRITSAN 2 trial (table 7) randomised patients with GPA or MPA that were in remission after induction treatment with CYC, RTX or MTX to receive either biomarker ‘tailored’ or fixed interval remission maintenance treatment with RTX.14 The ‘tailored’ arm received 500 mg RTX at randomisation and afterwards only if CD19-positive B cells or previously negative ANCA (by indirect immunofluorescent test (IFT) or ELISA) reappeared, or if ANCA levels significantly increased (≥2 dilution steps in IFT or doubled quantitative ELISA for MPO or PR3-ANCA). These biomarkers were measured in 3 monthly intervals. The treatment phase was 18 months. Patients in the fixed arm received 500 mg RTX on days 0 and 14 and at months 6, 12 and 18. The primary end point was the number of relapses at month 28. The number of relapses was not significantly different but numerically higher in patients receiving tailored RTX compared with the fixed-dose group. Since the number of relapse events was lower than anticipated, the trial is underpowered to exclude non-inferiority of a tailored approach. Two hundred forty-eight RTX infusions compared with 381 RTX infusions were given in the tailored versus fixed-dose group (n=81 subjects in each group). Of 22 relapsing patients, 7 (31.8%) had negative ANCA throughout the trial, 11 (50%) had always negative circulating B cell counts and 4 (18.2%) had negative ANCA and no detectable circulating B cells.
In the ongoing MAINTANCAVAS trial (table 7), patients with AAV in remission under RTX-induced continuous B cell depletion for 2 years were included and randomised to receive RTX maintenance treatment either at B cell return or at significant rise of ANCA levels.102 An interim analysis published as abstract reported relapse-free survival to be significantly higher in the B cell-driven compared with the ANCA-driven RTX treatment group.
The MAINRITSAN 3 trial (table 7) re-randomised patients from the MAINRITSAN 2 trial that were in remission at month 28 (including those with a minor relapse during MAINRITSAN 2 that required only increase of GC) to receive RTX 500 mg or placebo at months 0, 6, 12 and 18. Relapse-free survival at month 28 after randomisation was significantly higher in the RTX compared with the placebo group with similar rates of AEs.
Reduced levels of immunoglobulins have been reported in patients with AAV treated with RTX, which in some cases makes treatment with intravenous immunoglobulins necessary.7 37 84 122 Low baseline immunoglobulin levels seem to increase the risk of subsequent hypogammaglobulinaemia under treatment.
In summary, efficacy of RTX is higher than AZA for remission maintenance in AAV (LoE 1b). Prolonged RTX maintenance treatment for 36 months is more effective than 18 months (LoE 1b). Available evidence is insufficient to rule out inferiority of a biomarker-driven RTX treatment compared with a fixed administration at 6 months intervals. Hypogammaglobulinaemia (in some cases requiring immunoglobulin substitution) can develop under treatment with RTX (LoE 1b).
Maintenance treatment with belimumab
The randomised BREVAS trial (table 7) compared belimumab and placebo added to maintenance treatment with AZA and GC after remission induction with GC and RTX or CYC.52 The BREVAS trial did not demonstrate a significant difference in relapse rates, but relapse rates were low in the placebo group limiting the possibility of showing benefit of belimumab. The trial was terminated early.
In summary, the use of belimumab has not been shown to reduce relapse rates in GPA and MPA (LoE 1b).
Maintenance treatment with trimethoprim-sulfamethoxazole
Two meta-analyses (table 6) assessed the effect of trimethoprim-sulfamethoxazole (TMS) for remission maintenance treatment in GPA. Walters et al compared data from two RCTs,15 whereas Monti et al also included non-randomised intervention studies.67 No significant difference in remission rate or relapse risk of GPA was reported with both meta-analytical strategies.
In summary, pooled data from meta-analyses show no efficacy of TMS for maintenance treatment in GPA (LoE 1a).
Several landmark trials that improved the treatment strategies in AAV have been published since the last update of the EULAR recommendations for the management of AAV.1
For several areas of disease treatment evidence has accumulated: several meta-analyses comparing remission induction for AAV have been published. Continuous oral CYC and intravenous pulsed CYC show a similar efficacy for initial remission induction.15 16 The benefit of lower relapse risk with oral CYC comes at the cost of some increased toxicity. Meta-analyses also demonstrate similar overall efficacy for remission induction with RTX or MMF when compared with CYC. Several lessons on remission induction have been provided by the evidence since the 2016 version of the AAV recommendations: first, two RCTs comparing MMF and CYC5 13 suggest that MMF may not be as effective as CYC, which may be especially important to consider in patients with organ-threatening or life-threatening disease or higher relapse risk (eg, PR3-positive patients). Second, RTX is more effective than CYC for remission induction in patients with relapsing AAV.94 Third, two RCTs have demonstrated low- or reduced-dose GC schemes to be non-inferior to high-dose or standard-dose schemes, resulting in similar remission rates but lower rates of infectious complications.2 6 Fourth, a novel therapeutic agent, avacopan, has been demonstrated to allow rapid tapering and discontinuation of GCs during induction treatment, resulting in lower GC-induced adverse reactions.53
The role of PLEX for AAV remains controversial. Negative results of the PEXIVAS trial are in contrast to earlier RCTs like the MEPEX trial, which found PLEX to reduce the rate of death or ESKD.2 123 Meta-analyses pooling RCTs of PLEX in AAV reported contradictory results (table 5).15 16 27 96 100 101 Their results are dependent on methodology and inclusion criteria. The inclusion of observational non-randomised studies in some meta-analyses results in higher heterogeneity and increases the RoB. Meta-analyses that are limited to RCTs, including the results of PEXIVAS, suggest a lowered risk of ESKD at 1 year, but not during long-term follow-up, and an increased risk of infectious complications associated with PLEX used in active renal AAV. However, potential sources of bias remain: some of the included RCTs predate the classification criteria or diagnostic tests (ANCA) used to define trial populations nowadays. Furthermore, the introduction of new agents and treatment strategies may reduce the visible effect of PLEX additional to that achieved by drug treatment, which may result in less pronounced effects of PLEX in more recent trials. To summarise, the evidence on PLEX that has accumulated since the 2016 EULAR recommendations has decreased the enthusiasm for this treatment modality in AAV.
Evidence to refine maintenance treatment strategies for AAV has continued to accumulate. First, the superiority of RTX compared with AZA as maintenance treatment that was established after induction treatment with CYC by the MAINRITSAN trial,121 has now been expanded to situations when remission is induced with RTX.84 Prolonged maintenance treatment with both, RTX or AZA over a period of 36–48 months results in lower rates of relapse.3 7 Biomarker-driven retreatment of RTX is feasible but may result in a greater relapse risk.14 The optimal duration, intensity and personalisation of treatment remains to be further defined.
Data guiding the management of refractory disease remain scarce and this complex situation warrants detailed clinical workup and expert consultation.
The strength of our approach includes comprehensive literature search based on PICO questions by a group of expert clinicians and patient research partners, critical review of the literature and formal quality assessment. Some limitations need to be considered: first, our results are limited to the articles in English; moreover, most available studies have at least some remaining RoB: several investigator-initiated RCTs are unblinded (even though end points like ESKD or death are solid even in case of unblinded treatment). Second, the majority of meta-analyses has flaws in two or more critical domains of the AMSTAR 2 quality assessment instrument, lowering the overall confidence in the results. Third, the complexity and heterogeneity of AAV and the applied treatment protocols makes unbiased comparisons in retrospective study designs difficult. However, despite the rarity and complexity of AAV, major progress has been made in the last years by several well-performed landmark trials that provide high-quality evidence that refined and further developed treatment approaches.
The findings of this SLRs provide an up-to-date summary of available studies covering treatment strategies in GPA and MPA and highlight open questions and unmet needs in their management. The provided data supported the development of the 2022 EULAR recommendations for the management of AAV.17
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Patient consent for publication
The authors wish to thank the librarian Oliver Weiner (Medical Department of the Kiel University Library, Kiel, Germany) for advice and assistance, Susanne Blödt (AWMF Institute for Medical Knowledge-Management, Berlin, Germany) for helpful discussions regarding methodical aspects of the SLR as well as Max Yates (Norwich Medical School, University of East Anglia, UK) and Chetan Mukhtyar (Norfolk and Norwich University Hospital, UK) for providing evidence tables from the previous guideline update.
JHS and BS-A are joint first authors.
JHS and BS-A contributed equally.
Contributors BS-A and JHS conducted the SLR under supervision of the methodologists (RAL and GT). DJ, BH, GT, SM and RAL were members of the steering committee and provided substantial methodological advice. JHS and BS-A drafted the first version of the manuscript and subsequent revisions. All authors were involved in the formulation and discussion of the evidence and reviewed the manuscript and evidence tables. The final version of the manuscript was approved by all authors. The guarantor for this manuscript is JHS.
Funding This project was funded by EULAR. DJ was supported by the NIHR Cambridge Biomedical Research Centre.
Competing interests JHS received research grants from the John Grube Foundation and the Deutsche Gesellschaft für Rheumatologie (German Society for Rheumatology). BH received speaker fees and/or consultancies from AbbVie, Amgen, AstraZeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. DJ received speaker fees and/or consultancies from Amgen, AstraZeneca, BMS, Boehringer, Chemocentryx, GSK, InflaRx, Janssen, Novartis, Roche, UCB and Vifor. RAL received speaker and/or consulting fees and/or grants from AbbVie, BMS/Celgene, Chemocentryx, Chugai, GSK, InflaRx, Pfizer Global, Roche and Vifor.
Provenance and peer review Not commissioned; externally peer reviewed.
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