• 1.

    Furuta S, Jayne DRW. Antineutrophil cytoplasm antibody-associated vasculitis: Recent developments. Kidney Int 2013; 84:244249. doi: 10.1038/ki.2013.24

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Halbwachs L, Lesavre P. Endothelium-neutrophil interactions in ANCA-associated diseases. J Am Soc Nephrol 2012; 23:14491461. doi: 10.1681/ASN.2012020119

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Jayne DRW, et al.. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 2017; 28:27562767. doi: 10.1681/ASN.2016111179

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Jayne DRW, et al.. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021; 384:599609. doi: 10.1056/NEJMoa2023386

  • 5.

    Walsh M, et al.. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020; 382:622631. doi: 10.1056/NEJMoa1803537

  • 6.

    Kronbichler A, et al.. Frequency, risk factors and prophylaxis of infection in ANCA‐associated vasculitis. Eur J Clin Invest 2015; 45:346368. doi: 10.1111/eci.12410

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Flossmann O, et al.. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011; 70:488494. doi: 10.1136/ard.2010.137778

  • 8.

    Robson J, et al.. Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: Long-term data from the European Vasculitis Study Group trials. Rheumatology (Oxford) 2015; 54:471481. doi: 10.1093/rheumatology/keu366

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    McGregor JAG, et al.. Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am Soc Nephrol 2012; 7:240247. doi: 10.2215/CJN.05610611

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Goupil R, et al.. Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol 2013; 8:416423. doi: 10.2215/CJN.07300712

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Charlier C, et al.. Risk factors for major infections in Wegener granulomatosis: Analysis of 113 patients. Ann Rheum Dis 2009; 68:658663. doi: 10.1136/ard.2008.088302

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Smith RM, et al.. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis 2020; 79:12431249. doi: 10.1136/annrheumdis-2019-216863

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Jayne D, et al.. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:3644. doi: 10.1056/NEJMoa020286

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    de Groot K, et al.. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009; 150:670680. doi: 10.7326/0003-4819-150-10-200905190-00004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Guillevin L, et al.. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014; 371:17711780. doi: 10.1056/NEJMoa1404231

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Charles P, et al.. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018; 77:11431149. doi: 10.1136/annrheumdis-2017-212878

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Charles P, et al.. Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2020; 173:179187. doi: 10.7326/M19-3827

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Smith RM, et al.. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis 2020; 79:12431249. doi: 10.1136/annrheumdis-2019-216863

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Smith R, et al.. A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease. Nephrol Dial Transplant 2020; 35 (Suppl 3):LB004. doi: 10.1093/ndt/gfaa146.LB004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Smith R, et al.. A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease [abstract]. Arthritis Rheumatol 2019; 71 (Suppl 10):806. https://acrabstracts.org/abstract/a-randomized-controlled-trial-of-rituximab-versus-azathioprine-after-induction-of-remission-with-rituximab-for-patients-with-anca-associated-vasculitis-and-relapsing-disease/

    • Search Google Scholar
    • Export Citation

ANCA-Associated Vasculitis Circa 2020–2021 The March of Advancement Continues

  • 1 Sam Kant, MD, and Duvuru Geetha, MBBS, MD, are affiliated with the Division of Nephrology, Department of Medicine, Johns Hopkins University of School of Medicine, Baltimore, MD.
Full access

Kidney involvement is a major complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), manifesting clinically as rapid decline in glomerular filtration rate and histologically by Pauci-immune crescentic (Figure 1) and necrotizing (Figure 2) glomerulonephritis.

Figure 1.
Figure 1.

Cellular crescents

Citation: Kidney News 13, 4

Extracapillary proliferation causes glomerular tuft deflation with disappearance of normal glomerular structure and occlusion of capillary lumina. This is better shown by Jones methenamine silver (JMS) staining (A) and periodic acid−Schiff (PAS) staining (B). (Image courtesy Paride Fenaroli)
Figure 2.
Figure 2.

Glomerular fibrinoid necrosis at Jones methenamine silver (JMS) staining

Citation: Kidney News 13, 4

Silver staining hallmarks glomerular basement membranes (GBMs) and allows recognition of rupture (arrows) of GBM (A) and Bowman capsule (B), whereas fibrinoid necrosis appears as eosinophilic material. A small (A) and a larger (B) cellular crescent (stars) are also noted, as a result of membrane rupture. (Image courtesy Paride Fenaroli)

Over the last two decades, a number of randomized controlled trials have been conducted in AAV through collaboration of international experts in vasculitis. These trials have provided solid evidence for effective immunosuppressive therapy for remission induction and maintenance of remission. The focus has now turned to mitigating treatment-related adverse effects, along with treatment and prevention of disease relapse. Trials involving AAV were among the most fervently discussed topics in 2020. These trials not only looked to refine longstanding practices in the management of AAV but also added to our understanding of the disease.

Steroid avoidance on the anvil

Steroid avoidance has been a major goal in medicine and specifically in the management of AAV. Inhibition of the complement cascade is an attractive alternative to steroids for a variety of autoimmune diseases. In AAV, C5a and the C5a receptor (C5aR) have been implicated in pathogenesis by their effect on neutrophils and vascular endothelial cells (1, 2). Avacopan, an oral C5aR antagonist, may be the answer in this quest for steroid avoidance in AAV. A phase 2 trial (CLEAR) demonstrated that this agent was efficacious in replacing high-dose steroids in patients with newly diagnosed or relapsing AAV treated with cyclophosphamide or rituximab (3). Most recently, the ADVOCATE (A Phase 3 Clinical Trial of CCX168 [Avacopan] in Patients with ANCA-Associated Vasculitis) trial (n = 331) compared oral avacopan (n = 166) to oral prednisone (n = 165) in patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis after induction with either rituximab or cyclophosphamide (4). Patients in both groups had similar demographic and clinical characteristics—most importantly, similar organ involvement and induction regimen. The following were pertinent findings of this pivotal study:

  1. Avacopan treatment resulted in remission in patients with AAV receiving rituximab or cyclophosphamide/azathioprine and was noninferior to prednisone at week 26. However, it was superior to prednisone in sustained remission at week 52 (primary outcome).

  2. A significant reduction in steroid-related adverse effects was observed in the avacopan arm in comparison to prednisone arms, with accompanied acceptable safety profile of avacopan. (Adverse effects included abnormal liver function tests, serious infections, and worsening of vasculitis.)

To PLEX or not to PLEX

Medicine has always advanced when the status quo has been questioned. One such trial is PEXIVAS (Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody [ANCA]-Associated Vasculitis) (5). This was the largest AAV trial to date (n = 704): a 2-by-2 factorial, randomized by design, evaluated the use of plasma exchange (PLEX) compared with no PLEX and standard versus reduced dose oral glucocorticoids in patients with severe disease. Cyclophosphamide (84%) was the predominant induction therapy with 16% receiving rituximab. (All patients received methylprednisone as part of an induction regimen.) The study design ensured even distribution of myeloperoxidase (MPO)- and proteinase-3 (PR3)-positive patients, along with those with severe kidney and pulmonary disease in the treatment groups.

One of the pivotal findings of the trial was that a reduced dose steroid regimen was associated with reduced risk of serious infections at 1 year and was noninferior to the standard dose regimen. This is especially pertinent since infections are the leading cause of mortality in the early phases of treatment and continue to be a major contributor to morbidity and mortality in the long term (6, 7). It has already been established that steroids are associated with increased infectious risk and progressive organ damage in patients with AAV (8−11).

PLEX was not associated with a significant difference in the primary composite outcome of death from any cause or end-stage kidney disease (ESKD) or the secondary outcomes of sustained remission, serious adverse events, or serious infections at 1 year, including in patients with severe kidney or pulmonary disease. There are important caveats associated with these findings that warrant further discussion.

  • Kidney biopsy was not an entry criterion for the study. Therefore, we cannot truly assess acuity of disease to actually ascertain who would benefit from PLEX.

  • A subgroup analysis (n = 191) of nonsevere (n = 130; hazard ratio [HR] 0.64, confidence interval [CI] 0.33−1.24) and severe (n = 61; HR 0.64, CI 0.28−1.64) pulmonary hemorrhage, defined by oxygen saturation <85% while breathing ambient air or requiring mechanical ventilation, trended toward a possible benefit from PLEX, albeit not statistically significant. This was likely because relatively few patients with severe pulmonary hemorrhage were enrolled (<10% of total trial participants), a population that has been traditionally treated with PLEX.

Although this trial shows that PLEX may not be indicated in most patients with mild to moderate AAV disease (devoid of pulmonary hemorrhage and/or creatinine >5.6 mg/dL requiring dialysis), the jury is still out about its use in patients with severe kidney disease and/or diffuse alveolar hemorrhage.

The rituximab maintenance conundrum

Disease relapse remains a significant challenge in AAV, occurring in over 50% of patients within 5 years, with the majority suffering treatment-related toxicity (12−14). The MAINRITSAN (Efficacy Study of Two Treatments in the Remission of Vasculitis) trial indicated that, following remission induction with cyclophosphamide, rituximab was superior to azathioprine for relapse prevention (15). However, this was followed by an increase in relapse risk after rituximab withdrawal, with a mean time to relapse of 2 years after the rituximab dose. MAINRITSAN 2 (Comparison Study of Two Rituximab Regimens in the Remission of ANCA-Associated Vasculitis) answered the question of frequency of rituximab dosing by demonstrating that relapse rates were similar for tailored and scheduled rituximab, with fewer infusions in the tailored group (16). In 2020, MAINRITSAN 3 (Comparison between a Long-Term and a Conventional Maintenance Treatment with Rituximab) showed that extending rituximab maintenance therapy by another 2 years was associated with reduced relapse risk compared to standard maintenance therapy (17).

The appropriate maintenance regimen in patients with relapsing disease was provided with further clarity in the same year. The RITAZAREM (Rituximab Vasculitis Maintenance Study) trial recruited patients with relapsed AAV whose remission was re-induced with rituximab and glucocorticoids. Patients were then randomized in a 1:1 ratio to receive either rituximab (1000 mg every 4 months for 5 doses) or azathioprine (2 mg/kg/day) as maintenance therapy.

The authors recently published results of the induction-phase findings from the trial, demonstrating treatment with rituximab and glucocorticoids achieved a remission rate of 90% by the fourth month (18). The initial results of the maintenance phase (rituximab vs. azathioprine) were reported at the American College of Rheumatology and European Renal Association conferences. Rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. Twenty months after randomization, 13% of patients in the rituximab group had experienced a relapse compared to 38% of patients in the azathioprine group (19, 20). This trial has added more nuance to the care of patients with relapsing disease, which may represent a separate phenotype of disease.

Conclusion

A collaborative effort by nephrology and rheumatology has resulted in significant strides in the understanding of pathogenesis of disease and improvement in outcomes by continual innovation in management strategies. The next frontier lies in stratification of patient factors that might influence treatment response and evaluation of the use of biomarkers and predictors of relapse, allowing for more tailored treatment protocols with minimal side effects without compromising efficacy to improve outcomes in AAV.

Sam Kant reports no disclosures. Duvuru Geetha has the following disclosures: site principal investigator for the ADVOCATE trial and consultant to ChemoCentryx (manufacturer of Avacopan) and Aurinia Pharmaceuticals Inc.

References

  • 1.

    Furuta S, Jayne DRW. Antineutrophil cytoplasm antibody-associated vasculitis: Recent developments. Kidney Int 2013; 84:244249. doi: 10.1038/ki.2013.24

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Halbwachs L, Lesavre P. Endothelium-neutrophil interactions in ANCA-associated diseases. J Am Soc Nephrol 2012; 23:14491461. doi: 10.1681/ASN.2012020119

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Jayne DRW, et al.. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 2017; 28:27562767. doi: 10.1681/ASN.2016111179

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Jayne DRW, et al.. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021; 384:599609. doi: 10.1056/NEJMoa2023386

  • 5.

    Walsh M, et al.. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020; 382:622631. doi: 10.1056/NEJMoa1803537

  • 6.

    Kronbichler A, et al.. Frequency, risk factors and prophylaxis of infection in ANCA‐associated vasculitis. Eur J Clin Invest 2015; 45:346368. doi: 10.1111/eci.12410

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Flossmann O, et al.. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011; 70:488494. doi: 10.1136/ard.2010.137778

  • 8.

    Robson J, et al.. Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: Long-term data from the European Vasculitis Study Group trials. Rheumatology (Oxford) 2015; 54:471481. doi: 10.1093/rheumatology/keu366

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    McGregor JAG, et al.. Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am Soc Nephrol 2012; 7:240247. doi: 10.2215/CJN.05610611

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Goupil R, et al.. Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol 2013; 8:416423. doi: 10.2215/CJN.07300712

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Charlier C, et al.. Risk factors for major infections in Wegener granulomatosis: Analysis of 113 patients. Ann Rheum Dis 2009; 68:658663. doi: 10.1136/ard.2008.088302

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Smith RM, et al.. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis 2020; 79:12431249. doi: 10.1136/annrheumdis-2019-216863

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Jayne D, et al.. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:3644. doi: 10.1056/NEJMoa020286

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    de Groot K, et al.. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009; 150:670680. doi: 10.7326/0003-4819-150-10-200905190-00004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Guillevin L, et al.. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014; 371:17711780. doi: 10.1056/NEJMoa1404231

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Charles P, et al.. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018; 77:11431149. doi: 10.1136/annrheumdis-2017-212878

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Charles P, et al.. Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2020; 173:179187. doi: 10.7326/M19-3827

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Smith RM, et al.. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis 2020; 79:12431249. doi: 10.1136/annrheumdis-2019-216863

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Smith R, et al.. A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease. Nephrol Dial Transplant 2020; 35 (Suppl 3):LB004. doi: 10.1093/ndt/gfaa146.LB004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Smith R, et al.. A randomized, controlled trial of rituximab versus azathioprine after induction of remission with rituximab for patients with ANCA-associated vasculitis and relapsing disease [abstract]. Arthritis Rheumatol 2019; 71 (Suppl 10):806. https://acrabstracts.org/abstract/a-randomized-controlled-trial-of-rituximab-versus-azathioprine-after-induction-of-remission-with-rituximab-for-patients-with-anca-associated-vasculitis-and-relapsing-disease/

    • Search Google Scholar
    • Export Citation
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