BOTTOM LINE

GPA and MPA are distinct necrotizing small-size vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) with overlapping features. GPA classically involves the upper respiratory tract (including destructive sinusitis), lungs (nodules) and kidneys (glomerulonephritis). MPA classically manifests as pulmonary-renal syndrome (glomerulonephritis and pulmonary hemorrhage) and can cause ILD. Both may cause peripheral neuropathy, inflammatory arthritis, and small-vessel vasculitis in skin or other organs. GPA is more frequently associated with positive anti-PR3 ANCA in ELISA, whereas MPA patients are more frequently positive for anti-MPO ANCA; however, both can be ANCA negative, and a positive ANCA result is not specific for AAV. Histology for GPA shows granulomatous, necrotizing vasculitis of small vessels; MPA is non-granulomatous with vasculitis of small vessels. Induction treatment for systemic severe GPA and MPA requires glucocorticoids (GC) plus cyclophosphamide or rituximab. Avacopan can now be also used, and helps reduce GC use. Maintenance therapy is based on rituximab (azathioprine or methotrexate, in case rituximab cannot be used); the place of long-term low-dose prednisone remains debated. Mortality remains around 20% at 5 years, mostly related to infections, and relapses still occur in >25% of survivors at 5 years.
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EPIDEMIOLOGY

	GPA	MPA
Prevalence	~50-250/1,000,000	~25-150/1,000,000
Incidence	5-30 cases/million person-years	5-15 cases/million person-years
Age, sex	45-65 years, equal sex ratio	55-75 years, equal sex ratio
Ethnicity	More frequent in countries with European ancestry	More frequent in Asian countries
	Within a multiethnic population, incidence is higher in Caucasians	Within a multiethnic population, incidence is higher in Caucasians
ANCA	PR3-ANCA+: 65–75%	PR3-ANCA+ : 10–20%
	MPO-ANCA+: 20–30%	MPO-ANCA+ : 60-85%
	ANCA- : 5%	ANCA- : 5–10%

• Risk Factors
  • Genetic
    • MHC-associated
      • HLA-DPB1 associated with PR3-AAV
      • HLA-DQ associated with MPO-AAV
    • Non-MHC associated
      • PTPN22 (common to PR3-AAV, MPO-AAV, and other rheumatological diseases)
      • SERPINA1 (encodes α1-antitrypsin), PPTN3 (encodes PR3)
  • Environmental
    • Infection: neutrophil extracellular trap (NET) formation, molecular mimicry
    • Colonization: nasal Staph. aureus colonization may increase risk of risk of relapse in GPA
    • Geography: incidence of AAV is lower towards equator
    • Exposure to silica dust, cattle, and hydrocarbon solvents.

CLINICAL FEATURES

— Terms

• ANCA-negative ANCA vasculitis:
  • The clinical syndrome of GPA, MPA, or EGPA; however, ANCA is negative
• Single Organ Disease:
  • ANCA-associated vasculitis limited to one organ (ex: renal-limited vasculitis)
• Limited GPA:
  • GPA without severe organ/life-limiting disease. Usually only ENT symptoms.
  • May become severe over time.

GPA and MPA share many overlapping clinical features, though sometimes with different prevalence. Certain specific manifestations (below) are more suggestive of either GPA or MPA.

— OVERLAPPING FEATURES IN GPA and MPA

• Systemic
  • Fever, malaise, myalgias, anorexia, weight loss
  • GPA 70-100%,
    MPA 55-80%
• Skin
  • Petechiae and purpura of lower extremities
  • Focal necrosis and ulceration
  • Other: urticaria, livedo, nodules; infrequent erythema nodosum, pyoderma gangrenosum neutrophilic dermatoses
  • GPA and MPA: ~25-35%
• Renal
  • Pauci-immune focal and segmental necrotizing crescentic GN, usually first 2 years of disease onset; more likely to occur if ANCA positive
  • May have asymptomatic active sub-nephrotic urinary sediment with casts, variable renal injury
  • GPA 70-80%,
    MPA 80%
  • Subset of patients have renal-limited single-organ ANCA vasculitis (i.e.: vasculitis of the kidney only)
• Neurological
  • Peripheral
    • Mononeuritis multiplex, often involving superficial peroneal, deep peroneal, ulnar, and median nerves.
    • GPA < MPA:
      GPA 11-44%,
      MPA 55-79%
  • Central
    • GPA
      • Sinonasal disease may cause oculomotor dysfunction, mastoiditis, optic neuritis, cranial nerve palsy (most often CN II, VI, VII), pachymeningitis, and pituitary gland dysfunction.
      • Intracranial disease may cause intracerebral ischemia/hemorrhage in different territories
    • MPA
      • Intracerebral ischemia/hemorrhage, pachymeningitis, PRES or spinal cord involvement
    • GPA > MPA:
      GPA 7-11%, MPA rare
• Other
  • VTE (~10% develop VTE typically in first months after diagnosis, usually when disease is active/flaring), gastroenteritis, colitis, myo/pericarditis, inflammatory arthritis, urethritis, prostatitis, parotiditis, increased risk cardiovascular events

— GPA: more common manifestations

• Upper respiratory tract
  • Ear:
    Otitis media, otorrhea, deafness, polychondritis
  • Nose and sinuses:
    Crusting, ulcers, rhinorrhea, purulent/bloody discharge, sinusitis, saddle-nose deformity, septal perforation
  • Mouth, throat:
    Oral ulcers, mucositis/gingivitis
  • GPA 90%,
    MPA 2-30% (non-erosive)
• Lower respiratory tract
  • Airway:
    Subglottic stenosis
  • Parenchyma:
    Nodules (solid and/or cavitary), pseudotumor, ILD (ILD is more common in MPA than GPA; CT chest reveals UIP, NSIP, organizing pneumonia, or unclassifiable ILD pattern)
  • Vascular:
    Diffuse alveolar hemorrhage, pulmonary embolism
  • Pleural:
    Pleural effusion/pleuritis
• Eye
  • Epi/scleritis, corneal ulcer, uveitis, optic neuropathy, retinal vasculitis, orbital pseudotumor
  • Ocular manifestations of AAV can present independently of CNS or sinus manifestations (i.e.: they can occur independent of anatomically adjacent manifestations); requires regular assessment.
  • Cataracts, from GC exposure, is common
• Limited GPA
  • Usually localized upper respiratory tract, no life/organ-threatening disease, no GI, ocular, or CNS disease
  • Subglottic stenosis can be a form of limited GPA, which can become life-threatening

— MPA: more common manifestations

• Lower respiratory tract
  • Parenchyma:
    ILD in up to 40% of patients (CT chest reveals UIP, NSIP, organizing pneumonia, or unclassifiable ILD pattern)
  • Vascular:
    Diffuse alveolar hemorrhage, pulmonary embolism
  • Pleural:
    Pleural effusion/pleuritis

INVESTIGATIONS

• CBC
  • May have anemia (of chronic inflammation or if GI or lung alveolar bleeding), leukocytosis, thrombocytosis
• ALT, CK
  • Usually normal
  • ALT may be elevated due to drug toxicity (ex: cyclophosphamide, methotrexate)
• Creatinine, urinalysis, urine albumin:creatinine ratio or 24h urine
  • Creatinine may be elevated +/- active urine sediment (ex dysmorphic RBC, casts).
  • At diagnosis:
    • All patients require screening creatinine and urinalysis with urine albumin:creatinine ratio
  • At follow-up
    • All patients previously treated with cyclophosphamide require urinalysis every 3-6 months for several years to screen for cyclophosphamide-induced bladder malignancy
    • Urine studies should be repeated routinely as part of clinical assessment to monitor for disease activity and disease/treatment related renal damage
    • See Adjunctive Therapy and Monitoring below
• CRP (and ESR)
  • Often elevated with active vasculitis, but this is non-specific
• C3, C4
  • Usually normal
• ANCA Antibodies
  • A high-quality, antigen-specific immunoassay for PR3-ANCA and MPO-ANCA is the preferred method of ANCA measurement
  • GPA
    · PR3-ANCA 65-75%
    · MPO-ANCA 20-30%
    · ANCA negative 5%
  • MPA
    · PR3-ANCA 20-30%
    · MPO-ANCA 55-65%
    · ANCA negative 5-10%
  • Notes
    • By indirect immunofluorescence (no longer done routinely), anti-PR3 ANCA usually corresponds to cANCA (cytoplasmic), and anti-MPO ANCA usually corresponds to pANCA (perinuclear).
    • Prognosis: anti-PR3 ANCA is associated with a higher risk of relapse; anti-MPO ANCA predicts a worse prognosis (higher mortality) versus anti-PR3 or ANCA-negative vasculitis
    • Antibody tire level can reflect disease activity in some patients
    • Seroconversion (a positive ANCA becomes negative) after induction treatment suggests a better prognosis; persistently positive PR3-ANCA is a risk factor for relapse
    • Anti-MPO is less specific for AAV than Anti-PR3 ANCA.
      • Many other disease cause ANCA positivity, especially an anti-MPO ANCA (see differential below)
• Other Antibodies
  • ANA, RF
    • Not associated with GPA or MPA, may be positive by chance
  • Anti-GBM antibody
    • Screen anti-GBM antibody in all patients with new GN or alveolar-hemorrhage/GN (“pulmonary renal syndrome”); double positive (both ANCA and anti-GBM) patients exist
    • See: Anti-GBM Disease
    • If anti-GBM positive, patient requires plasma exchange as part of induction treatment
• Other screening at diagnosis or if flare
  • Always screen for infection, may include: blood cultures, Hep B/C, HIV; TB testing if risk factors for infection
  • Bronchoalveolar lavage not routine; may be done if severe respiratory symptoms to investigate for infection or alveolar hemorrhage
  • EMG: as indicated if needed to investigate neuropathy and possible targeting of nerve biopsy
• Imaging
  • Chest
    Screen all patients with pulmonary symptoms with Chest X-ray and/or CT Chest (CT is much more sensitive for ILD than chest X-ray)
  • Other
    CT sinuses/orbit/neck as indicated
• Biopsy
  • Biopsy whenever possible for diagnosis; some defer a renal biopsy if the patient presents with the clinical syndrome of GPA/MPA, is ANCA+, GBM-, and has active urinary sediment (i.e.: some defer the renal biopsy if the patient has a very high likelihood of clinical diagnosis). Biopsy is preferable, but should not delay prompt treatment.
  • Biopsy targets: skin, renal (if active GN), lung (usually by video-assisted thoracoscopy), sural nerve (if suspecting neuritis).
  • Transbronchial or nasal biopsies are usually not high yield, not helpful, and non-specific.
  • Findings
    • Renal: pauci-immune segmental necrotizing glomerulonephritis
    • Skin: leukocytoclastic vasculitis (non-specific finding, but compatible with an AAV diagnosis in the right clinical context)
    • Lung: chronic inflammation, capillaritis;
      • Granulomatous inflammation suggests GPA over MPA

DIAGNOSIS

Suspect AAV in patients with constitutional symptoms and a constellation or organ dysfunction reasonably explained by small- to medium-vessel inflammation including in the respiratory tract (sinusitis, deafness, hoarseness, cough, hemoptysis), kidneys (GN), skin (petechiae/purpura), or neuropathy. Screen urine for evidence of renal vasculitis and screen other organs as indicated (ex: CT for lung manifestations, EMG for nerve manifestations). Order ANCA testing, though some patients may be ANCA negative, and ANCAs alone are not specific for AAV. Seek a biopsy whenever possible to support diagnosis: usually renal, skin, or lung biopsy. Stratify the patient according to the extent and severity of disease in order to allow for tailored therapy. Be sure to rule out infection and malignancy. The ultimate diagnostic label should be in terms of clinical and serological profile (i.e.: the clinical syndrome followed by ANCA antibody result); for example: “GPA with negative ANCA”, “MPA, MPO-ANCA positive”.

DIFFERENTIAL DIAGNOSIS

• Infection
  • Infections can cause positive ANCA, especially bacteremia
  • Infective endocarditis mimics AAV:
    renal failure (from sepsis or immune-complex GN), hemoptysis (from septic emboli to lung), skin rash (Osler nodes mistaken for petechiae), and ANCA positivity
  • Tuberculosis can mimic AAV:
    granulomatous inflammation, lung masses, and rarely ANCA positivity
  • COVID-19:
    57% ANCA+ in hospitalized COVID-19 patients; rare de novo AAV reported after COVID infection (as was reported after influenza).
  • Infections in AAV patients on immunosuppression can mimic a flare of AAV 
    (ex: pneumonia, otitis media, UTI).

Always screen for infection at diagnosis and if suspected vasculitis flare

• Malignancy
  • Lymphoma, leukemia, myeloproliferative and myelodysplastic disorders can mimic GPA/MPA (ex: lymphoma can cause granulomatous lymphocytic infiltration and be associated with ANCA+)
  • Vasculitis treatment can further increase cancer risk (ex: CYC, AZA)
• EGPA
  • Cardinal features of EGPA not seen in GPA/MPA:
    • Asthma, eosinophilia, hyper IgE
  • Features distinguishing EPGA from GPA specifically:
    • ENT manifestations: EGPA causes non-destructive manifestations, GPA is often destructive.
    • Lung disease: EGPA causes migratory non-cavitating lung densities, GPA can cause fixed cavitating densities
• Other Glomerular Disease
  • Membranous nephropathy
  • IgA nephropathy
  • Anti-GBM disease (Formerly “Goodpasture”)
    • Always screen for anti-GBM antibody at diagnosis
    • If positive, patient likely requires plasma exchange as part of induction therapy
  • Lupus nephritis
• PAN
  • Cardinal features of PAN not seen in AAV: renal infarcts, renal artery stenosis, visceral microaneurysms.
  • Frequent features of AAV not seen in PAN: GN and ANCA positivity
  • PAN is very rare
• Medication-induced
  • Numerous drugs implicated in vasculitis, same also cause ANCA positivity (usually anti-MPO)
  • Some examples: PTU, hydralazine, minocycline, procainamide
  • Treatment: withdraw offending drug, steroids may be required for end organ inflammation
• Cocaine-related
  • Non-vasculitic manifestations of cocaine toxicity:
    • Sinonasal destruction & hemoptysis from vasoconstriction without vasculitis
  • Cocaine/levamisole-related necrotizing granulomatous ANCA vasculitis
    • Features include sinonasal destruction, significant skin vasculitis, hemoptysis, ANCA+.
    • Skin vasculitis is a frequent manifestation:
      • Retiform purplish plaques with a bright erythematous edge and necrotic center, painful hemorrhagic blisters
      • Predilection for lower limbs, ears, zygomatic arches and tip of the nose
    • Suspect cocaine/levamisole related AAV if:
      • Multiple positive serologies: anti-PR3, anti-MPO, atypical ANCA, ANA, RF, etc.
      • Manifestations rare/incompatible for GPA/MPA: hard palate erosion, ear pinna lesions with significant skin necrosis, leukopenia or thrombocytopenia (from levamisole related agranulocytosis)
    • Treatment is abstinence from cocaine; GC may be required for end-organ inflammation.
      • Treatment with CYC, rituximab, plasmapheresis, MTX, MMF have been reportedly used in a few severe cases.

CLASSIFICATION CRITERIA

AAV is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

GPA CLASSIFICATION CRITERIA (ACR/EULAR 2022)

Apply criteria to classify a patient as having GPA when a diagnosis of small– or medium-vessel vasculitis has already been made

Exclude diagnoses mimicking vasculitis prior to applying criteria

Score ≥5 is needed to classify GPA. Sensitivity 93%, Specificity 94%

—Clinical Criteria

Nasal involvement: bloody discharge, ulcers, crusting, congestion, blockage, or sept defect/perforation	+3
Cartilaginous involvement (inflammation of ear or nose cartilage, hoarseness, stridor, endobronchial involvement, saddle nose deformity)	+2
Conductive or sensorineural hearing loss	+1

—Lab, imaging, biopsy criteria

Positive cANCA or anti-PR3	+5
Pulmonary nodules, mass, or cavitation on chest imaging	+2
Granuloma, extravascular granulomatous inflammation or giant cells on biopsy	+2
Inflammation, consolidation, or effusion of the nasal/paranasal sinuses, or mastoiditis on imaging	+1
Pauci-immune GN on biopsy	+1
Positive pANCA or anti-MPO	-1
Serum eosinophilia ≥1×100/L	-4

MPA CLASSIFICATION CRITERIA (ACR/EULAR 2022)

Apply criteria to classify a patient as having GPA when a diagnosis of small– or medium-vessel vasculitis has already been made

Exclude diagnoses mimicking vasculitis prior to applying criteria

Score ≥5 is needed to classify MPA. Sensitivity 91%, Specificity 94%

—Clinical Criteria

Nasal involvement: bloody discharge, ulcers, crusting, congestion, blockage, or sept defect/perforation

-3

—Lab, imaging, biopsy criteria

Positive pANCA or anti-MPO	+6
Fibrosis or interstitial lung disease on chest imaging	+3
Pauci-immune GN on biopsy	+3
Positive cANCA or anti-PR3	-1
Serum eosinophilia ≥1×100/L	-4

DISEASE MEASURES

• More often used for research purposes, not usually used in daily clinic
  • Disease activity score: BVAS (Birmingham vasculitis activity score), BVAS/WG
  • Damage score: VDI (Vasculitis Damage Index)

TREATMENT

GENERAL PRINCIPLES

• Stratify GPA/MPA patients based on extent of organ manifestations and degree of severity
  • Consider using validated score such as BVAS or BVAS/WG
• Tailor treatment based on stratification, age, and comorbidities
• Treatment generally follows a regimen of Induction and Maintenance
• Existing guidelines (especially CanVasc and KDIGO) can provide some guidance, but every patient needs an individualized approach  

INDUCTION

— Glucocorticoids

• Initial Dose
  • Prednisone 1mg/kg/day (max 80mg/day)
  • Methylprednisolone 0.5-1g IV/day x 3 days is sometimes given if severe organ/life threatening disease, but efficacy unproven and carries higher risk adverse effects (diabetes and infections)
• Taper
  • Start prednisone taper within 2 weeks of induction
  • “Classic taper”
    • Roughly tapered to 15-25mg/d by 12 weeks and 5mg/d by 24 weeks
  • “Reduced-dose taper”
    • Roughly tapered to 7.5-12.5mg/day by 12 weeks, and 5mg/d by ~15-20 weeks
  • If inducing with Avacopan combination: aim to taper and discontinue prednisone by week 4 of Avacopan
  • Canvasc Physician Tools for a GC tapering resource

— Additional Agents: Combine GC with an additional agent at time of induction

• Limited Disease
  • Definition: limited GPA (see above) or non-severe non-renal GPA/MPA with no life or organ-threatening disease
  • Methotrexate 25mg/week (for limited GPA, preferred)
    or
    Mycophenolate mofetil 1-1.5g BID (limited GPA/MPA)
  • Rituximab can be considered also, directly first-line or as second-line agent
• Generalized Disease
  • Either RTX (rituximab) or CYC (cyclophosphamide) — RTX preferred.
    • RTX may be preferred if contraindications to CYC, high infertility risk, relapsing disease
    • May combine RTX with 1-year of Avacopan 30mg BID
      • Accelerate prednisone taper to discontinuation by 4 weeks of Avcopan
    • RTX
      • RTX 1g IV day 0 and day 14,
        or
      • RTX 375mg/m² weekly x 4
    • CYC
      • CYC 1.5-2mg/kg/day PO x 3 months (until remission), then 1.5mg/kg/day oral x 3 months (max daily dose is 200mg/day);
        or
      • CYC 15mg/kg/day IV q2 weeks x 3, then q3 weeks x 3-6 months (max dose of 1200mg per IV bolus)
      • Lifetime cumulative dose should not exceed 25g of CYC
    • PLEX
      • PLEX (plasma exchange) is not routinely recommended.
      • Initiate PLEX if concomitant anti-GBM antibody.
      • Some may consider PLEX for patients with severe renal injury (might delay initiation of dialysis) or pulmonary hemorrhage (controversial)
• CYC IV dose adjustments for age, renal clearance

Age	IV CYC dose, Creatinine 150-300 mmol/L	IV CYC dose, Creatinine 300-500 mmol/L
<60	15 mg/kg	12.5 mg/kg
60-70	12.5 mg/kg	10 mg/kg
>70	10 mg/kg	7.5 mg/kg

• CYC IV dose adjustment for age (alternate strategy)
  • Age >65: fixed dose CYC 500mg IV monthly x 6 months (alternate option to above)
• CYC PO dose adjustment for age
  • ↓25% dose for >60 years-old
  • ↓50% dose for > 75 years-old

If a patient induced with CYC flares, re-induce with RTX.

If a patient induced with RTX flares, re-induce with CYC.

MAINTENANCE

• First line
  • RTX 1g IV q4-6 months
    • May consider re-infusion based on
      • ANCA titre rise, or
      • If ANCA switches from negative to positive, or
      • If repopulation of CD19+ B-cell subsets (not recommended if no clinical evidence of disease flare)
• Other agents
  • Azathioprine 100-150mg daily (roughly 2mg/kg/day; inferior to RTX), or
  • Methotrexate 20-25mg weekly (dose for renal clearance; similar efficacy to azathioprine ), or
  • Leflunomide 10-20mg daily (dose for renal clearance), or
  • Mycophenolate mofetil 1000-1500mg BID (less preferred)
• Duration
  • RTX: treat for minimum 2-4 years, longer for high risk patients (see risks for relapse below)
  • AZA, MTX. LEF, or MMF: minimum 2-4 years, longer for high risk patients (see risks for relapse below)
  • Long-term (>2 years) low-dose prednisone (5mg daily): controversial, but likely needed if maintenance is not based on RTX.
  • Avacopan: unclear if benefit >1 year; can be continued, but no solid data at present

If flare: always consider the differential of infection in an immunosuppressed patient as the cause of presentation

Specific considerations

• Sinonasal involvement:
  • Nasal rinses and topical therapies (antibiotics, lubricants, glucocorticoids)
  • Avoid picking at nasal crusts
• Nasal septal defects
  • Reconstructive surgery can be offered, if disease is in remission and patient desires
• Subglottic and/or endobronchial stenosis
  • Consider treating with immunosuppression rather than surgical dilatations and intralesional GC alone
• Mass lesions
  • Consider treating with immunosuppression rather than surgical removal (ex: orbital pseudotumour, parotid glands, brain, lugs)

ADJUNCTIVE THERAPY AND MONITORING

• Screening and vaccines
  • Bladder cancer:
    • Urinalysis q3-6 months for several years to screen for bladder malignancy if induced with CYC
  • Skin cancer:
    • Routine skin exams for non-melanoma skin cancer 
  • Bone density:
    • Consider screening in patients with additional risk factors
  • Immunoglobulin levels:
    • Patients on RTX getting severe/recurrent infections
    • If hypogammaglobilinemia before RTX dose (ex, IgG <2-3g/L, or if repeated infections), consider supplemental immunoglobulins (multidisciplinary decision, made with Clinical Immunology)
  • Vaccinations:
    • Pneumococcal, influenza, COVID, shingles vaccine for everyone (ideally 5 months post RTX infusion and 4 weeks prior to next RTX infusion)
• PJP prophylaxis
  • Trimethoprim-sulfamethoxazole DS 1-tab Monday/Wednesday/Friday
    • Use SS instead of DS if CKD with creatinine >200 micromol/L
  • Initiation: start with induction therapy
  • Duration: at least 3 months following CYC cessation or  6 months following RTX cessation
  • If allergy or intolerance: dapsone 50mg daily or atovaquone 1500mg daily as alternative
• GI Ulcer
  • Add a PPI if on high dose steroids and if other risk factors for GI ulcer
• Cardiovascular risk screening
  • Increased risk of coronary artery disease and ischemic stroke, especially in first year after diagnosis
  • Risk is correlated with disease activity and ANCA type

EVALUATING TREATMENT RESPONSE

• Structured clinical assessments to detect symptoms and signs of recurrent disease
  • Review and bedside assessment
  • Routine labs and urinalyses with urine ACR
  • May consider BVAS to help quantify disease activity and VDI to quantify disease and treatment-related damage
• Serial ANCA monitoring
  • ANCA positivity not necessarily reflective of disease activity in all patients
  • Not generally recommended to re-dose rituximab maintenance based on ANCA titers alone
  • If ANCA was positive at disease onset,  the persistence, rise or re-appearance of ANCA may suggest patients whom require closer follow-up (see risk of relapse below)
• Serial CD19+ B cell monitoring
  • Not recommended to re-dose rituximab maintenance based on CD19+ titers alone

PROGNOSIS

• Frequent comorbidities
  • Infection
    • Particularly in first year of treatment; see Adjunctive Therapy and Monitoring above regarding decreasing infection risk
  • Venous thromboembolism
    • ~10% develop VTE typically in first months after diagnosis, when the AAV is active
  • Cancer risk
    • Due to exposure to cyclophosphamide and other immunosuppressive medications
    • Particularly non-melanoma skin cancer and (with CYC) urothelial malignancy
    • Cancer risk appears to be decreasing over time with less use of cyclophosphamide and more use of rituximab
  • Osteoporosis:
    • Due to GC exposure
  • Cardiovascular events (coronary artery disease and ischemic stroke)
    • Highest risk in first year after diagnosis
    • Correlated with disease activity and ANCA type
• Relapse Risk
  • Relapses are frequent.
    • At 4 years: 30% GPA relapses, 10% MPA relapse.
  • Increased risk of relapse
    • Prior relapse
    • GPA
      (HR 1.44, 95% CI 1.06-1.94)
    • Anti-PR3 ANCA
      (HR 1.62, 95% CI 1.39-1.80)
    • Cardiac involvement
      (HR 1.59, 95% CI 1.07-2.37)
  • Decreased risk of relapse
    • MPA
      (HR 0.72, 95% CI 0.59-0.89)
    • ANCA negative after induction
      (HR 0.63, 95% CI 0.42-0.95)
    • Low renal function (Cr >200umol/L or eGFR <30)
      (HR 0.39, 95% CI 0.22-0.69)
• Quantification of prognosis (survival)
  • 2009 Five Factor Score can be applied for prognosis

Factor	Point
Age >65	+1 point
Cardiac symptoms	+1 point
Gastrointestinal involvement	+1 point
Renal insufficiency (stabilized peak Cr ≥150 umol/L)	+1 point
Absence of Ear/Nose/Throat symptoms (only score for GPA and EGPA patients)	+1 point

Total 5-factor score	5-year mortality
0	9%
1	21%
≥2	40%

• Common causes of death
  • Complications from therapy (infection)
  • Complications from disease (renal or respiratory failure)
  • Cardiovascular events
• Mortality and Survival
  • 5-year survival 70-80%
  • Mortality of adults with MPA: 2.7X general population (France).
  • Mortality of adults with GPA: 2.0X general population (France).

REFERENCES

Ai, S., Liu, X., Chen, G., Zhang, Y., Bai, X., Qin, Y., Miao, Q., & Li, X. (2022). Characteristics and Diagnostic Challenge of Antineutrophil Cytoplasmic Antibody Positive Infective Endocarditis. The American journal of medicine, 135(11), 1371–1377. https://doi.org/10.1016/j.amjmed.2022.06.015

Alba, M. A., Flores-Suárez, L. F., Henderson, A. G., Xiao, H., Hu, P., Nachman, P. H., Falk, R. J., & Charles Jennette, J. (2017). Interstital lung disease in ANCA vasculitis. Autoimmunity reviews, 16(7), 722–729. https://doi.org/10.1016/j.autrev.2017.05.008

Almaani, S., Fussner, L. A., Brodsky, S., Meara, A. S., & Jayne, D. (2021). ANCA-Associated Vasculitis: An Update. Journal of clinical medicine, 10(7), 1446. https://doi.org/10.3390/jcm10071446

Bataille PM, Durel CA, Chauveau D, Panes A, Thervet ÉS, Terrier B. Epidemiology of granulomatosis with polyangiitis and microscopic polyangiitis in adults in France. J Autoimmun. 2022 Dec;133:102910. doi: 10.1016/j.jaut.2022.102910. Epub 2022 Sep 12. PMID: 36108505.

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