AAV and Small Vessel Vasculitis


    • Clinical Picture 
        • POSS - SS are GPA specific 
          • Pulm nodule 
          • Orbital Pseudotumor 
          • Sinonasal Inf 
          • Subglottic inflam 
          • SS Scleritis and sensorineural hearing loss more specific of GPA than MPAK
        • PAD same for both PN, AH, Digit ischemia
    • Lab: ANCA (c-ANCA, p-ANCA), anti-PR3, anti-MPO 
      • Antibodies to PR3 or MPO are sufficiently specific that they can be considered diagnostic in cases in which vasculitis is highly likely by other criteria. Examples of such clinical settings include digital ischemia (diagnosed by physical examination); noncompressive neuropathy (diagnosed by nerve conduction studies); and alveolar hemorrhage (diagnosed by either bronchoalveolar lavage or witnessed hemoptysis plus CT imaging consistent with diffuse bleeding). 
      • In particular, p-ANCA immunofluorescence has poor specificity for AAV, whereas anti-MPO antibodies have high specificity for AAV.
    • Biopsy
      • There is a difference of opinion in one key area. Some experts believe that a kidney biopsy should be performed whenever possible to confirm pauci-immune glomerulonephritis and give prognostic information derived from the degree of permanent damage,93,98,99 whereas other experts might argue that red blood cell casts in the urine in the setting of anti-PR3 or anti-MPO antibodies are sufficient.
      • A biopsy definitive for GPA should include necrotizing extravascular granuloma in addition to small-vessel vasculitis, but this combination of features is seen in a minority of biopsy specimens
      • Similarly, the combination of small-vessel vasculitis and eosinophil-rich necrotizing granuloma is seen in a minority of biopsy specimens in EGPA
    • UA  
    • The poor specificity of p-ANCA alone (i.e., without positive testing for antibodies to MPO) is well known. However, positive testing for anti-MPO or anti-PR3 antibodies has been well documented in three conditions other than AAV: endocarditis,100 systemic lupus,101 and use of cocaine adulterated with levamisole.102
    • Other Small vessel vasculitis: Other than the characteristic disease in the kidney (similar although perhaps not identical in all forms of ANCA-associated vasculitis),98,103 the disease of MPA in other organs is difficult to distinguish from that of other forms of small-vessel vasculitis by light microscopyThe absence or paucity of immune complex deposition by immunofluorescence is helpful but not definitive, because immune deposits may have been consumed by phagocytes in lesions more than 48 hours old.
    • For EGPA: A high circulating eosinophil count is also often the clue that a patient has EGPA or HES rather than merely asthma and nasal polyposis.

  • The best evidence that ANCA are directly pathogenic comes from a mouse model in which anti-MPO antibodies (produced by immunizing Mpo−/− mice with mouse MPO) produce pauci-immune GN when transferred into normal mice.154 (Kelley and Friesetins - K and F)) 
  • Efforts to produce an analogous model using PR3 have not been successful (K and F)
  • T cell immunity is implicated in any process that results in high-affinity antibodies, but in addition, CD4+ T cells are found in the necrotizing granulomatous lesions in GPA and are likely involved in macrophage activation and neutrophil recruitment locally.161
  • The number of circulating proteins related to immunity, inflammation, vascular injury, and tissue repair is so large in highly active GPA and MPA that it is difficult to obtain insight into pathophysiology from biomarker studies
  • Challenges in AAV moving forward: Clinicians and investigators alike would benefit from an improved understanding of the role of ANCA in disease pathogenesis, identification of clinically actionable biomarkers of disease activity, and the development of more targeted therapies to reduce treatment toxicity

  • RAVE Trial NEJM 2010 Rituximab vs Cyc (non-inferiority trial)
  • Multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. 
  • Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
  • Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001).
  • The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage.
  • Conclusion: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.

  • Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis RITUXVAS NEJM 2010
  • We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.
  • The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m2 of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00).
  • Efficacy of Remission-Induction Regimens for ANCA-Associated Vasculitis RAVE-ITN Research Group NEJM 2013
  • Conclusion: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months
  • In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months.
  • A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide–azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells.

  • Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis List of authors. French Vasculitis Study Group NEJM 2014
  • Methods: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide–glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both).
  • Results: The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).
  • Conclusions: More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. 

  • MAINRITSAN 2 2018 Fixed vs tapering dose of rituximab for maintenance therapy Ann Rheum Dis (ARD) French Vasculitis Study Group
  • Objective: To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs).
  • Methods: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group.
  • Conclusions: AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions

  • PEXIVAS Trial NEJM 2020
  • In patients with severe ANCA-associated vasculitis, PEXIVAS compared the efficacy of plasma exchange with no plasma exchange with respect to death or ESKD. The trial also compared a reduced-dose regimen of glucocorticoids with a standard-dose regimen over the first 6 months of the treatment period to determine whether the reduced dose was noninferior to the standard dose with respect to death or ESKD.

  • Mepolizumab (anti-IL 5)  vs Placebo for EGPA NEJM May 2017
  • Inclusion criteria

    • EGPA diagnosis: participants who have been diagnosed with EGPA for at least 6 months based
      on the history or presence of: asthma plus eosinophilia (>1.0x109/L and/or >10% of leucocytes) plus at least two of the following additional features of EGPA:
      • A biopsy showing histopathological evidence of eosinophilic vasculitis, or o Perivasculareosinophilicinfiltration,oreosinophil–richgranulomatous o Inflammation
      • Neuropathy, mono or poly (motor deficit or nerve conduction abnormality)
      • Pulmonary infiltrates, non–fixed
      • Sino–nasal abnormality
      • Cardiomyopathy (established by echocardiography or MRI)
      • Glomerulonephritis (hematuria, red cell casts, proteinuria)
      • Alveolar hemorrhage (by bronchoalveolar lavage)
      • Palpable purpura
      • Positive test for ANCA (MPO or PR3).

      • Relapsing disease: Participant must have a past history of at least one confirmed EGPA
      relapse (i.e., requiring increase in oral corticosteroid [OCS] dose, initiation/increased dose of immunosuppressive therapy or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.
      • Japan-only definition of relapsing disease: participant must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation of intravenous (IV) prednisolone (or equivalent), initiation/increased dose of immunosuppressive therapy, initiation/increased dose of IV immunoglobulin (IVIG) or hospitalization) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.

      • Refractory disease:Either: failure to attain remission (Birmingham Vasculitis Activity Score [BVAS; scale 0– 63]=0 and OCS dose ≤7.5 mg/day prednisolone or equivalent) within the prior 6 months following induction treatment with a standard regimen, administered for at least 3 months.
      a. Participants who have received a cyclophosphamide induction regimen may be included a minimum of 2 weeks after the last dose of daily oral cyclophosphamide, or
      3 weeks after the last dose of pulsed IV cyclophosphamide prior to baseline (Visit 2), if their total white blood count is ≥4x109/L (tested at the local laboratory, if necessary) prior to randomization.
      b. Participants who have received an azathioprine, methotrexate, or mycophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to baseline (Visit 2).
      c. Participants who have received an induction regimen comprising glucocorticoids alone may be included only if they have failed to attain remission after 3 months of treatment
      of relapsing OR refractory disease defined as:

      AND the glucocorticoid dose is ≥15 mg/day prednisolone or equivalent for the 4 weeks prior to baseline (Visit 2).
      Or: Within 6 months prior to screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) while tapering OCS, occurring at any dose level ≥7.5 mg/day prednisolone or equivalent

    • Enrolled participants were at least 18 years of age, had received a diagnosis of relapsing or refractory eosinophilic granulomatosis with polyangiitis at least 6 months previously, and had been taking a stable dose of prednisolone or prednisone (≥7.5 to ≤50.0 mg per day, with or without additional immunosuppressive therapy) for at least 4 weeks before the baseline visit.
B-VAS (Birmingham vasculitis assessment score)

Presence of poor prognostic factors were excluded. Includes 
Absence of sinus disease
? Absence of Cardiac involvement 
Pulm involvement 
Renal Involvement