AAV and Small Vessel Vasculitis


    • Clinical Picture 
        • POSS - SS is GPA specific 
          • Pulm nodule 
          • Orbital Pseudotumor 
          • Sinonasal Inf 
          • Subglottic inflam 
          • SS Scleritis and sensorineural hearing loss more specific of GPA than MPAK
        • PAD is the same for both PN, AH, and Digit ischemia
    • GPA (reference: Uptodate)
      • ENT or UPPER Respiratory tract: 90 percent in GPA versus 35 percent in MPA
        • nasal crusting, sinus pain, chronic rhinosinusitis, nasal obstruction, persistent rhinorrhea, purulent/bloody nasal discharge, oral and/or nasal ulcers, polychondritis, otitis media, earache, otorrhea, conductive and/or sensorineural hearing loss
        • bone and cartilage destruction resulting in a saddle nose deformity - more in GPA than mpa
      • TRACH/PULM or LOWER Respiratory tract: 
        • TRACHEOBRONCHIAL DISEASE:  tracheal or subglottic (subglottic stenosis is mc tracebronchial manifesation (8-50% patients) or can also be a sole manifesation) or/bronchial ulceration to stenosis (asymptomatic to Cough/Dyspnea/Hemoptysis/Post-obstructive PNA), mass lesions (inflammatory pseudotumors), tracheobronchial malacia, and tracheoesophageal fistulae 
        • ILD (more common with MPA, can precede systemic vasculitis symptoms) (present in 12% at onset and 15% at follow-up, in a retrospective review of 49 patients, 82 % had MPA and 18 % had GPA ) (UIP, CPFE (combined pulmonary fibrosis and emphysema)
        • Pulmonary artery stenosis 

        • sx: hoarseness, cough, dyspnea, stridor, wheezing, hemoptysis, or pleuritic pain
        • ds: pulmonary consolidation and/or pleural effusion; interstitial lung disease, complicated by pulmonary fibrosis and pulmonary arterial hypertension
        • nodules, patchy or diffuse opacities and fleeting pulmonary infiltrates, and hilar adenopathy
      • RENAL
        • evident glomerulonephritis was present in only 18 percent of patients at presentation in a study by NIH, but glomerulonephritis subsequently developed in 77 to 85 % pt
        • asymptomatic hematuria that can remit and relapse, rpgn, variable degree of proteinuria - read more in up-to-date. RPGN is a typical renal manifesation
      • SKIN:  30 to 50 percent of patients with GPA or MPA
        • a most common skin lesion is purpura involving the lower extremities that may be accompanied by focal necrosis and ulceration, urticaria, livedo reticularis, and nodules. Occasional patients with erythema nodosum, pyoderma gangrenosum, and Sweet syndrome 
      • NEURO: multiple mononeuropathies, sensory neuropathy, cranial nerve abnormalities, central nervous system mass lesions, external ophthalmoplegia, and sensorineural hearing loss, Meningeal disease is most commonly associated with granulomatous inflammation of the central nervous system; peripheral nervous system involvement is noted in approximately 15 percent of patients with GPA and 70 percent of those with MPA
      • OPTHAL/ORBITAL:  conjunctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, retinal vasculitis, uveitis, retro-orbital pseudotumor and nasolacrimal duct obstruction 
      • OTHER
        • tumor-like: tumor-like masses outside the lung can occur. Among 20 such reported cases, the most common extrathoracic locations were the breast and kidney. Failure to consider vasculitis in the differential diagnosis in such cases may lead to unnecessary surgery, including nephrectomy. Sometimes, a diagnosis of sarcoidosis or pulmonary tuberculosis will be made mistakenly.
        •  the gastrointestinal tract, heart (pericarditis, myocarditis, conduction system abnormalities), lower genitourinary tract (including the ureters and prostate), parotid glands, thyroid, liver, or breast, deep venous thrombosis (DVT)
    • 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, 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
    • Urine Analysis  
    • Approach: 
      • Dyspnea and radiographic changes of DAH: work up expediated - 
        • Generalt tests: CBC with diff, INR, PT, aPTT, UA along with exam for RBC casts, COVID Tests, Blood Cx, and tests for Influenza, BNP, BAL (visible hemorrhage, hemosiderin-laden macrophages, eosinophils, microbiologic cultures/immunoassays, cytology)
        • If condition allows, HRCT before BAL 
        • Tests for immune-mediated disease: ANCA, Anti-GBM antibody, ANA , C3, C4 (?CH50), CK, RF, Anticardiolipin antibodies, anti-beta-2-glycoprotein I, and/or a lupus anticoagulant
        • May be needed: Anti-histone ab, ASO, UDS, Leptoprioris, Skin biopsy, Lung Biopsy
    • 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, systemic lupus, and use of cocaine adulterated with levamisole.
    • Other Small vessel vasculitis: Other than the characteristic disease in the kidney (similar although perhaps not identical in all forms of ANCA-associated vasculitis), 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



For remission induction,  based on RAVE Trial  (N Engl J Med 2010; 363:221-232),  rituximab (dose of 375mg/m2 weekly for 4 weeks. 

One to three pulses of methylprednisolone (1000 mg each), followed by prednisone at a dose of 1 mg per kilogram per day. 

IV Pulse steroid for rapidly progressive glomerulonephritis, pulmonary hemorrhage, mono neuritis multiplex, or optic neuritis

Glucocorticoid taper: ADVOCATE Trial dose vs PEXIVAS short course vs PEXIVAS long course vs LoVAS



The dose was tapered so that by 5 months, all patients who had a remission without disease flares had discontinued glucocorticoids.

Hep B and C, TB. Quant Gold 

Recommend PJP prophylaxis with Bactrim (depending on renal function)


25 OH vitamin D level. I would start 1000 IU/25 mcg D3.

1200 mg calcium/day. Not necessarily given as a single dose.  Eg.  chocolate milk has 200 mg of calcium. If one drinks 3-4 per day (600-800 mg).  All we need will be an additional 400 mg that can be obtained from a well-rounded diet alone.    Will increase dose if 25 OH vitamin D level is very low)

N Engl J Med 2020;382:622-31.



Our patient would have been excluded from LoVAS as eGFR is < 15 (was 14) on admission. 
Our patient would have been included in the PEXIVAS trial : So, will do PEXIVAS low dose 
Our patient would not have been included the ADVOCATE Trial as well 

Section S3. Cyclophosphamide Induction Regimen

Standard induction therapy with cyclophosphamide (CYC) will be prescribed for at least 13 weeks and no more than 26 weeks. As the experience of using either oral or intra-venous (IV) routes of administration varies between centres and there is no apparent difference in efficacy or safety, the study protocol will allow the use of either oral or IV CYC. The CYC regimens will be identical for all treatment groups.

A starting dose of 15 mg/kg/pulse will be used for pulse CYC (maximum 1.2 g/dose) or 2 mg/kg/day for oral CYC (maximum 200 mg/day) with reductions made for age and renal function in each group according to previous trials conducted in Europe. Oral CYC will be administered daily with the recommendation for morning administration of full dose, if tolerated. Pulse CYC will be administered IV at a frequency of every two weeks for the first 3 doses then every three weeks thereafter. Modifications to dose and frequency will be made in the case of leucopenia.

For patients undergoing PLEX, PLEX will not occur for at least 24 hours following an IV dose of CYC.

For patients receiving PLEX and daily CYC (oral or IV), on days when PLEX is performed, CYC will be given following PLEX. PLEX will not be performed for at least 12 hours following a dose of oral CYC.

Full (complete) blood counts will be performed according to local protocol but the following minimum is recommended: patients receiving oral CYC should have their blood count monitored weekly for the first four weeks and weekly for four weeks after any dose adjustment and every other week thereafter. Patients receiving pulse CYC should have their blood count monitored 10 to 14 days after each dose and within 1 day prior to each dose.

Concomitant use of mesna is optional and left to the discretion of the investigator and local practice.

Dosage Modifications for Renal Function and Age

Starting doses of CYC should be adjusted for advanced age or reduced renal function. Renal function may change over the course of the trial and medication dosages may be adjusted to reflect these changes.

Dosage Modification for Leucopenia

For pulse CYC the WBC count should be determined within 1 day prior to an IV pulse CYC. If the WBC count is <4x109/L, the CYC dose should be postponed until the WBC count is >4x109/L and the dose should be reduced to 75% of the planned dose (planned dose x 0.75).

The WBC count nadir should also be determined 10 to 14 days after the pulse dose is given. If the nadir is <3x109/L, the next pulse should be reduced even if the next pre-dose WBC count is >4x109/L. For a nadir

pg. 10 Walsh et al. Plasma Exchange and Oral Glucocorticoids Dose in Severe ANCA-associated Vasculitis

<2x109/L, the next dose should be 60% of the previous dose (previous dose x 0.6). For a nadir of 2- 3x109/L, the next dose should be 80% of the previous dose (previous dose x 0.8).

Similar dose reductions to those made for leucopenia may be made for thrombocytopenia and anemia at the investigator’s discretion. Dose alterations should also be made in the event of infectious complications.

Section S4. Rituximab Induction Regimen

Rituximab may be prescribed to patients as induction remission therapy. Rituximab will be prescribed as 4 intravenous doses of 375 mg/m2 according to the following schedule:

  1. Dose 1 within first 14 days of participation

  2. Subsequent doses should occur 7 days after the previous dose. Doses may, however, occur 5 to 14

    days to accommodate practical considerations of administering rituximab and to accommodate plasma exchange. All doses must be given within 42 days of the first dose. PLEX should not be given within the first 48 hours after administering rituximab.

Prophylaxis against infusion reactions must be given as 100 mg of intravenous hydrocortisone or equivalent with or without an anti-histamine agent immediately preceding the first rituximab infusion, and local guidelines should be followed before subsequent infusions of rituximab.

Story of AAV treatment: 

The CYCLOPS trial (European Vasculitis Study Group; Ann Intern Med. 2009;150(10):670  )showed that with a much lower cumulative dose of CYC by IV CYC pulse instead of PO daily CYC, you could achieve the same benefit. The dose used in the CYCLOPS trial was 15 mg/kg every 2 to 3 weeks plus prednisone. RAVE Trial NEJM 2010 Rituximab vs Cyc showed that Rituximab is non-inferior to CYC for remission induction. The dose used in the RAVE trial for Rituximab was 375 mg per square meter of body-surface area per week for 4 weeks. Of note, the RAVE trial used the PO dosing of CYC and not IV CYC. The difference at 6 months was 64% vs 53%, and among relapse patients, it was 67% vs 42 %. The addition of pulse CYC (2 doses) to Rituximab in  RITUXVAS NEJM 2010  had improved remission at 12 months at 76 %. In fact, CYC followed by AZA had an even higher percentage of remission i.e 82% compared to  Rituximab / 2 dose CYC IV pulse in this study. Yet, CYC fb AZA is not the preferred treatment option. That is because of the Rituximab versus Azathioprine MAINRITSAN Trial by French Vasculitis Study Group NEJM 2014. This study showed among patients who achieve remission, it is sustained at 95% vs 69 % with RTX maintenance vs CYC fb AZA at 22 months. Put other way, 5 % patients (n=3) had relapse with RTX compared with 29 % with CYC fb AZA. RTX maintenance regimen used in MAINRITSAN is  500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry. In this study, the patients had achieved remission induction with CYC/prednisone. Patients in RTX group did get RTX at the beginning of the remission induction as was used in RITUXIVAS which makes sense as RITUXIVAS had higher remission induction than in RAVE or CYCLOPS. Note that the dose used here is much smaller than used in RAVE/ RITUXIVAS trial though. 

Summary thus far. RTX is non-inferior for remission induction (RAVE), and is also better for maintenance (MAINRITSAN). But, should patient receive CYC with RTX for induction as used in MAINRITSAN to achieve higher remission at 22 months?

Yet, 2 questions were unanswered. Who gets PLEX for remission induction, and who dose of steroid tapering is good as cumulative steroid taper has significant AEs. This was answered by PEXIVAS Trial NEJM 2020 . PLEX was not beneficial, and rapid steroid taper was non-inferior for disease relapse. 

In patient whom RTX is not an option for maintenance, AZA is always a good maintenance regimen as was used in CYCAZERAM. Note AZA was also used in in RITUXIVAS  or MAINRITSSAN 1. In patients who cannot be on AZA, then based on WEGENT Trial, MTX is an alternative to AZA.  


Ulrich Specks, Mayo Clinic 

John Stone MGH 

Peter A. Merkel, BU 

Rachel Johns UK 

Remission Induction

  • Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. (CYCLOPS Trial)
  • EUVAS (European Vasculitis Study Group) 
  • Ann Intern Med. 2009;150(10):670
  • INTERVENTION: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone.
  • Results: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia
  • RAVE Trial NEJM 2010 Rituximab vs Cyc (non-inferiority trial
  • Nine centers enrolled 197 ANCA-positive patients
  • 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.
  • Questions answered: 
  • Why to do Rituximab?
  • Why not to do PO CYC? Btw also answered by CYCLOPS 
  • Also, gave the steroid regimen for initial use of steroid. 

  • Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis RITUXVAS NEJM 2010
  • compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. 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, 
  • The median the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m2 of body-surface area.
  • Sustained remission: 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) (P=0.68). 
  • SAE: 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). 
  • Death: 6/33 patients in the rituximab group (18%) and 2/11 patients in the control group (18%) died (P=1.00).
  • Questions answered: 
  • Why not to do IV CYC Pulse? Is it because of the mortality otherwise remission at 12 months seems so much better than in RAVe Trial - 76% vs 48%. In fact CYC had 82 % remission - the answer actually comes better from the 2014 French vasculitis group study that shows 95% sustained remission 

An important consideration when reviewing both of these trials is that patients with alveolar hemorrhage requiring mechanical ventilation or with serum creatinine levels >4 mg/dL were excluded from enrollment in the RAVE trial.(Uptodate)

  • 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.
  • Questions answered: What is better for maintenance?
  • Rituximab: Changes of relapse is answered ? Remain on remission at 64%, 48 %, 39% at 6, 12, 18 mths 
  • CYC PO followed by AZA: Remain on remission at 53%, 39%, 33 % at 6, 12, 18 mths

  • Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis List of authors. French Vasculitis Study Group NEJM 2014 MAINRITSAN 1 Study 
  • 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. 
  • Questions answered: Since single cycle RTX although better than CYC fb AZA is better for maintenance, only 39% of patients remain at remission at 18 mths, will a repeat dose of RTX improve remission at 22 months?
  • Rituximab: 5 % patient (n=3) had relapse with RTX compared with 29 % with CYC fb AZA. 

  • 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 non-inferior to the standard dose with respect to death or ESKD.
  • Questions answered: 
  • 1: Who benefits from Plasma exchange?
  • 2: How quickly to taper steroid?  
Reduced-dose glucocorticoid tapering regimen for patients with GPA and MPA
WeekPatient weight
<50 kg50 to 75 kg>75 kg
3 to 4202530
5 to 6152025
7 to 812.51520
9 to 101012.515
11 to 127.51012.5
13 to 1467.510
15 to 16557.5
17 to 18557.5
19 to 20555
21 to 22555
This table provides an example of a reduced-dose, oral glucocorticoid-tapering regimen for a patient with new-onset or relapsing GPA or MPA. Depending on the management by the treating clinicians, it can be initiated immediately or after a course of IV glucocorticoids. After week 22, further reduction in glucocorticoid dose is individualized based on treating provider and patient preference.
GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; IV: intravenous.
From: Walsh M, Merkel PA, Peh CA et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020; 382:622. 
Ref: Uptodate 


The CYC vs AZA for Early Remission Phase of Vasculitis (CYCAZAREM) trial, which included 155 patients

CYCAZEREM vs WGET (Etanercept)

Our results contrast with data from the Cyclophosphamide versus Azathioprine as Remission Maintenance Therapy for ANCA-Associated Vasculitis (CYCAZAREM) Study,31 a randomized comparison of cyclophosphamide with azathioprine for the maintenance of remission in ANCA-associated vasculitis. The CYCAZAREM Study found that 7 percent of patients had a severe relapse and 15 percent had a relapse of any severity, as compared with the respective rates of 22 percent and 57 percent in WGET. There are several explanations for the reported differences between these two trials.

In the CYCAZAREM Study, 39 percent of the patients had microscopic polyangiitis, a form of ANCA-associated vasculitis that is less likely to relapse than is Wegener's granulomatosis. Furthermore, in order to qualify as a disease flare, there had to be at least three minor manifestations of active disease, whereas WGET required only one. It is therefore conceivable that episodes of minor disease activity were undercounted in the CYCAZAREM Study. The longer follow-up in our trial (27 months, vs. 18 months in CYCAZAREM) may also have led to a higher percentage of observed disease flares. Perhaps most important, however, patients in the CYCAZAREM Study continued to receive 7.5 mg of prednisolone per day after the achievement of remission. In contrast, the WGET protocol called for the cessation of glucocorticoid therapy after six months.

The Wegener Granulomatosis-Entretien (WEGENT) trial found that AZA and MTX provide comparable efficacy and are similarly safe

Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.
N Engl J Med. 2014;371(19):1771. 
compared rituximab with AZA in 115 patients who had attained remission after initial therapy using CYC plus glucocorticoids; most patients were newly diagnosed rather than relapsed (80 versus 20 percent), had GPA rather than MPA (76 versus 20 percent), and had a positive PR3-ANCA rather than MPO-ANCA (70 versus 23 percent)
Rituximab was given as two 500 mg doses separated by 14 days at baseline and then again at months 6, 12, and 18. Azathioprine was given at a dose of 2 mg/kg per day for 12 months followed by 1.5 mg/kg per day for six months and then 1 mg/kg per day for four additional months. 
Treatment with rituximab produced a lower rate of major relapse as compared with azathioprine at 28 months (5 versus 29 percent). The number of serious adverse events was similar in both groups.

  • 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
  • Also, showed that CD19 test did not help minimize the relapse. Infact, half of the relaps in that arm occurred in patients with suppressed CD19. 


The International  Mcyophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) trial
JAMA. 2010;304(21):2381. Epub 2010 Nov 8. 
Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates.

  • Primarily affects small vessels 
  • Pathogenesis: 
    • EGPA- presentation and treatment may need to be pathophysiology dependent
      • Type 2 - TH2 or ILc2 - due to IL4, IL5, IL13. IL4 is involved in IgE presentation. 
      • Eosinophil Biology: IL5 is vital for eosinophil formation - production, ingression into circulation, and survival. Eosinophil predominant symptoms are best treated with Mepolizumab. 
        • Other mediators of eosinophil biology: GMCSF, IL3, recruitment (CCL25 or eotaxin)
      • TH2 component in asthma components: 
      • Humoral autoimmune component: If IgE is increased, or IgG4 is increased, then B cells inhibition (rituximab) may be of help ? 
    • Unclear why there is vascular and perivascular granuloma in some patients
    • Unclear on the role of complement in the EGPA ( where as studies have shown steroid sparing effect of complement inhibition effect of C5 inhibition Avacopan in non EGPA ANCA vasculitis)
  • Phase of Disease 
    • Prodromal - 3r/4th decade - asthma, allergic rhinitis,  atopic ds; usually precedes vasculitis phase by 8-10 yrs 
    • Eosinophilic phase - blood and including organs (lung, GI)
    • Vasculitic phase - The vasculitic phase may be heralded by nonspecific constitutional symptoms and signs, especially fever, weight loss, malaise, and lassitude.
  • Clinical features: 
    • Cardiac involvement: likely a vascular manifestation but there is myocardial infiltration from eosinophils based on data published by Andrew Churg. In contrast, Hyperesoniphilic syndrome (HES, Myoloid HES), there is endomyocardial fibrosis and involvement. This is probably not the dominant presentation in EGPA)
    • ENT:  serous otitis media, allergic rhinitis, nasal obstruction, recurrent sinusitis, and nasal polyposis, is reported in 70 to 85 percent patients with EGPA
      • Necrotizing lesions of the nasopharynx and upper airway are more characteristic of granulomatosis with polyangiitis (GPA), and are unusual in EGPA
    • Skin: Skin involvement is one of the most common features of the vasculitic phase of EGPA. Half to two-thirds of patients with EGPA have skin lesions, which usually appear as tender subcutaneous nodules on the extensor surfaces of the arm, particularly the elbows, hands, and legs
      • Skin lesions can also appear as a macular or papular erythematous rash or hemorrhagic lesions, including petechiae, palpable purpura, and extensive ecchymosis
    • CV: In a series of 383 patients with EGPA, 16 percent had a cardiomyopathy and 15 percent had pericarditis
      • valvular insufficiency, pericardial effusion, and heart failure were noted in 73, 50, and 41 percent, respectively
    • VTE : 8%
    • Neurologic: PN and MM (75%), MM patient more likely to have ANCA positive; various CNS manifestations can also occur 
    • Renal: In 83 %, RPGN in (50 % in 1 study of 116 patients) 
    • GI : GI bleeding, colitis, diarrhea 
    • MSK:  Myalgias, migratory polyarthralgias, and frank arthritis are less common, but may affect 40 to 50 percent of patients in the vasculitic phase of the disorder. Myositis can also rarely be a presenting symptoms. 
    • LN: LN up to 3 cm can be present 
  • Dx
    • ACR 1990 : four or more of these six criteria had a sensitivity of 85 percent and a specificity of 99.7 percent for EGPA
    1. Asthma (a history of wheezing or the finding of diffuse high pitched wheezes on expiration)
    2. Greater than 10 percent eosinophils on the differential leukocyte count
    3. Mononeuropathy (including multiplex) or polyneuropathy
    4. Migratory or transient pulmonary opacities detected radiographically
    5. Paranasal sinus abnormalities 
    6. Biopsy containing a blood vessel showing the accumulation of eosinophils in extravascular areas
    • Lanham
      • asthma, peak peripheral blood eosinophilia in excess of 1500 cells/microL, and systemic vasculitis involving two or more extra-pulmonary organs. In this classification, all three criteria must be met for a diagnosis of EGPA.
    • A question that arises in the categorization of patients with suspected EGPA is how to classify patients with asthma and blood eosinophilia >1500 cells/microL and/or ≥10 percent of leukocytes, but without definite evidence of vasculitis outside the lungs, nose, and sinuses. One proposal is to reserve the designation of EGPA for patients with asthma and blood eosinophils ≥1500 cells/microL (1.5 G/L) and/or ≥10 percent of leukocytes and one or more of the following [9]:

      Definite polyangiitis: Biopsy showing necrotizing vasculitis, biopsy showing necrotizing or crescentic glomerulonephritis, alveolar hemorrhage, palpable purpura, or myocardial infarction due to proven coronaritis

      Definite surrogates for vasculitis: Hematuria associated with red cell casts or >10 percent dysmorphic erythrocytes; hematuria with 2+ proteinuria; leukocytoclastic vasculitis/eosinophilic infiltration of an arterial wall on biopsy

      Mononeuritis or mononeuritis multiplex 

      Antineutrophil cytoplasmic antibody (ANCA) and systemic manifestations (eg, myocarditis, pericarditis, peripheral neuropathy, other renal disease, abdominal pain)

      This proposal suggests creating a new category called “hypereosinophilic asthma with systemic manifestations” for patients with asthma, hypereosinophilia (≥1500 cells/microL and/or ≥10 percent of leukocytes), and any systemic manifestation, but without ANCA, definite polyangiitis, a surrogate of polyangiitis, or mononeuritis.

    • EULAR 

  • 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.
  • EGPA- presentation and treatment may need to be pathophysiology dependent
    • Type 2 - TH2 or ILc2 - due to IL4, IL5, IL13. IL4 is involved in IgE presentation. IL5 is the cause for eosinophilia. Treat in such situation with Mepolizumab. 
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 

ANCA Tests : Ref: Uptodate 

PR3 and MPO are located in cytoplasmic azurophilic granules of neutrophils and the peroxidase-positive lysosomes of monocytes. Antibodies with target specificities for PR3 and MPO are called "PR3-ANCA" and "MPO-ANCA," respectively.

Two types of antineutrophil cytoplasmic autoantibody (ANCA) assays are in wide use:

IFA using alcohol-fixed buffy coat leukocytes (more sensitive)

ELISA, using purified specific antigens (more specific)


C ANCA pattern With the cytoplasmic ANCA (C-ANCA) pattern, the staining is diffuse throughout the cytoplasm. In most cases, antibodies directed against PR3 cause this pattern [9,10], but MPO-ANCA can occasionally be responsible.

P ANCA pattern The perinuclear ANCA (P-ANCA) pattern results from a staining pattern around the nucleus, which represents an artifact of weak ethanol fixation. With ethanol fixation of the neutrophil substrate, positively charged granule constituents rearrange themselves around the negatively charged nuclear membrane, leading to perinuclear fluorescence [3]. Among patients with vasculitis, the antibody responsible for this pattern is usually directed against MPO (and only occasionally PR3).

Immunofluorescence patterns in nonvasculitic conditions — Atypical ANCA patterns may be observed on immunofluorescence testing in patients with immune-mediated conditions other than systemic vasculitis (eg, connective tissue disorders, inflammatory bowel disease, and autoimmune hepatitis). These atypical ANCA patterns may be confused with P-ANCA patterns. However, ELISA testing for antibodies against MPO or PR3 is negative in such cases.

Pitfalls of interpreting immunofluorescence results

There is a subjective component to the interpretation of immunofluorescence assays because the tests are based upon visual interpretation of the immunofluorescence pattern;

Immunofluorescence results are not highly specific for the diagnosis of vasculitis. The C-ANCA pattern has a greater specificity than the P-ANCA pattern for vasculitis.

Antibodies to a host of azurophilic granule proteins can cause a P-ANCA staining pattern. These include antibodies directed against lactoferrin, elastase, cathepsin G, bactericidal/permeability-increasing protein (BPI), catalase, lysozyme, beta-glucuronidase, and others. A positive P-ANCA immunofluorescence staining pattern may also be detected in a wide variety of inflammatory illnesses and has a low specificity for vasculitis. A positive immunofluorescence assay should therefore always prompt testing by ELISA to determine the specific antibody (or antibodies) responsible for the pattern.

Because of the frequent difficulty in distinguishing the P-ANCA pattern of immunofluorescence from that caused by antinuclear antibodies (ANA), individuals with ANA frequently have "false-positive" results on ANCA testing by immunofluorescence. Typically, in patients who have a positive ANA, a positive P-ANCA is a false positive. However, pauci-immune necrotizing glomerulonephritis has been reported in patients with systemic lupus erythematosus (SLE) with positive P-ANCA, and ELISA testing should be performed in all such patients

To avoid false-positive P-ANCA tests, immunofluorescence assays should be routinely performed on both formalin- and ethanol-fixed substrates. This is because formalin-fixed neutrophils prevent the rearrangement of charged cellular components around the nucleus. The use of both cell substrates permits the distinction between antibodies causing a "true" P-ANCA pattern and those directed against the nuclear antigens (ANA)

Hydralazine — Hydralazine has been associated with two drug-induced systemic rheumatic syndromes:

Drug-induced lupus (see  "Drug-induced lupus")

Drug-induced ANCA-associated vasculitis, which is a potentially more serious condition

Solid-phase immunoassays — Solid-phase immunoassays (eg, ELISAs) are used for detection of specific antibodies to PR3 and MPO are commercially available and should be part of any standardized approach to the testing for ANCA. ELISAs are the most commonly used solid-phase assay but alternative solid-phase assays are also available [8].

PR3-ANCA and MPO-ANCA are associated with substantially higher specificities and positive predictive values than the immunofluorescence patterns to which they usually correspond (C- and P-ANCA, respectively)

False-positive ANCA