(aka Microscopic Polyarteritis, Polyangiitis Overlap Syndrome, Systemic Necrotizing Vasculitis, Allergic Vasculitis)

Epidemiology

• History: first reported in 1985 (described as Microscopic Polyarteritis) -> name later changed to Microscopic Polyangiitis in 1994 by consensus committee
  • Probably represents a variant of PAN (Note: PAN involves predominantly medium-sized vessels and typically spares the lung)
• Prevalence: second most common cause of pulmonary capillaritis with diffuse alveolar hemorrhage
• Age: average age of presentation: 50 y/o
• Sex: M>F

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Physiology and Pathology

• Small-Medium Vessel Necrotizing Vasculitis (involving arterioles/capillaries/venules): mixed inflammatory infiltrate without granulomas
  • Pulmonary Capillaritis: seen in 20-30% of cases
  • Organizing Pneumonia: may be seen
• Relative sparing of abdominal viscera
• Immunoglobulin and complement in vessel walls of skin lesions and normal skin

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Diagnosis

• OLB: may be necessary
  • Tissue Ab staining: negative
• ESR: elevated
• Serology
  • ANA: variable
  • Anti-DNA: negative
  • RF: variable
  • Immune complexes: positive in 45% of cases
  • C3/C4/CH50: normal
  • p-ANCA (perinuclear pattern, targeted mainly against myeloperoxidase): positive in 50-75% of cases
  • Anti-GBM: negative
  • HBsAg: may be positive
  • Antibodies to HBV and HCV: positive in 33% of cases
• CBC
  • Anemia (iron deficiency): usually present
  • Leukocytosis:
• Urinalysis: may be abnormal
• Renal Bx: focal segmental necrotizing glomerulonephritis (consistent feature)
  • Crescents

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Clinical Manifestations

(multi-system involvement with symptoms usually present for only days-weeks before presentation)

Renal Manifestations

(absence of HTN aids in differentiation from Polyarteritis Nodosa)

• Rapidly Progressive Glomerulonephritis: almost universal
• Crescentic Glomerulonephritis (80% of cases)

Constitutional Manifestations (common)

(may precede onset of renal disease by months)

• Weight Loss (>70%)
• Fevers (55%)

Derm Manifestations (35-60% of cases)

• Palpable purpura (common): leukocytoclastic vasculitis
• Papules
• Nodules
• Necrotic Ulcerations
• Vesiculobullous Lesions
• Splinter Hemorrhages

Neuro Manifestations (60% of cases)

• Mononeuritis Multiplex (10-50% of cases)
• Peripheral Neuropathy

Pulmonary Manifestations (10-30% of cases)

(usually severe and may be life-threatening)
(abence of asthma aids in the differentiation from Churg-Struass Syndrome)

• Diffuse Alveolar Hemorrhage (see [[Diffuse Alveolar Hemorrhage]]): occurs in 10-30% of cases
  • FOB (during diffuse alveolar hemorrhage): RBC’s, hemosiderin-laden macrophages
  • PFT’s (during diffuse alveolar hemorrhage): increased DLCO
  • CXR/Chest CT: diffuse or patchy alveolar infiltrates (interstitial infiltrates may appear with recurrent diffuse alveolar hemorrhage)
  • Symptoms: cough, dyspnea, chest pain, hemoptysis (may be absent initially in some cases, even after significant bleed)
• Pleural Effusion (see [[Pleural Effusion-Exudate]]): occur in 5-20% of cases
• Interstitial Lung Disease (see [[Interstitial Lung Disease-Etiology]]): uncommon (although may occur with recurrent diffuse alveolar hemorrhage)
  • Associated with high mortality rate
• Severe Irreversible Airflow Obstruction (see [[Obstructive Lung Disease]]): few case reports with obstruction occurring after recurrent diffuse alveolar hemorrhage
• Pulmonary Hypertension (see [[Pulmonary Hypertension]]): uncommon

Upper Airway Manifestations (5-30% of cases)

• Sinusitis: most common upper airway manifestation

Rheum Manifestations

• Arthritis
• Arthralgias/Myalgias (50% of cases)

GI Manifestations (35-55% of cases)

(relative sparing of abdominal viscera)

• Mucosal Ulcerations
• Abdominal Pain
• GI Bleeding
• Ischemia/Infarction (see Acute Mesenteric Ischemia)
• Diarrhea
• Visceral Aneurysms: rare

Ocular Manifestations (0-30% of cases)

• May be clinically silent

Cardiac Manifestations (10-15% of cases)

• CHF (see [[CHF]])
• Pericarditis (see [[Acute Pericarditis]])

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Prognosis

• 5-year survival: 45-75%
• Early mortality is 25% in presence of DAH
• Residual obstructive (emphysema has been reported in some cases, due to recurrent bleeds with neutrophilic damage to lung) and restrictive defects have been reported in survivors

Factors Associated with Poor Survival

• Cr >1.58
• Proteinuria >1g/day
• Severe GI involvement
• Cardiac involvement
• CNS involvement
• Diffuse Alveolar Hemorrhage

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Treatment

European Vasculitis Study Group Recommendations for Induction Therapy

(induction therapy is typically given until remission has been achieved or for the first 1 year)

• Limited Disease: localized upper airway disease
  • Constitutional Symptoms: no
  • Renal Function: Cr <1.4 mg/dL
  • Threatened Organ Function: no
  • Treatment
    • Corticosteroids or Methotrexate or Azathioprine
    • Alternatively: Bactrim alone has been recommended for this group , but efficacy is unproven
• Early Generalized Disease
  • Constitutional Symptoms: yes
  • Renal Function: Cr <1.4 mg/dL
  • Threatened Organ Function: no
  • Treatment Options
    • Corticosteroids + Cyclophosphamide
    • Corticosteroids + Methotrexate: NORAM Trial demonstrated that methrorexate is as efficacious as cyclophosphamide for the induction of remission in ealr generalized disease
• Active Generalized Disease
  • Constitutional Symptoms: yes
  • Renal Function: Cr <5.7 mg/dL
  • Threatened Organ Function: yes
  • Treatment
    • Corticosteroids + Cyclophosphamide: pulsed IV cyclophosphamide is as effective as PO cyclophosphamide (1 mg/kg/day) with fewer side effects
• Severe Disease
  • Constitutional Symptoms: yes
  • Renal Function: Cr >5.7 mg/dL
  • Threatened Organ Function: yes (diffuse alveolar hemorrhage, etc)
  • Treatment
    • Corticosteroids + Cyclophosphamide + Plasma Exchange
      • Addition of plasma exchangeis superior to pulsed high-dose teroids in restoring renal function in cases with severe renal impairment
      • This strategy may also be beneficial in the treatment of Diffuse alveolar hemorrhage
      • Other agents described in case reports that may have benefit in diffuse alveolar hemorrhage: activated human factor 7, extra-corporeal membrane oxygenation (ECMO) (used mainly to support patient until other therapies can take effect)
• Refractory Disease
  • Constitutional Symptoms: yes
  • Renal Function: any
  • Threatened Organ Function: yes
  • Treatment
    • Rituximab (see [[Anti-CD20 Therapy]]): has been demonstrated to be equivalent to cyclophosphamide in inducing remission and may be superior in terms of treating relapsed disease
      [N Engl J Med 2010; 363:221-232]
    • IVIG (see [[Intravenous Immunoglobulin]])
      • May be useful to treat residual or persistent disease after other therapy
      • Response to IVIG is transient
      • Side effects (such as renal insufficinecy) are frequent
    • Anti-Thymocyte Globulin (see [[Anti-Thymocyte Globulin]])

Maintenance Therapy

• Timing of Transition to Maintenance Therapy: controversial, some argue that patient should be converted to maintenance after remission has been achieved and others argue patient should be converted to maintenance after the first year of induction therapy
  • CYCAZA-REM Trial: patients with active generalized disease can be transitioned to PO cyclophosphamide maintenance to azathioprine once clinical remission has been achieved (using clinical criteria, generally within 3-6 months) -> no increase in relapse rates, disease activity scores, or change in renal function
• Regimens
  • Low-Dose Corticosteroids + Methotrexate
  • Low-Dose Corticosteroids + Azathioprine (2 mg/kg/day)
  • Cellcept
  • Leflunomide
  • Cyclosporine A
• Duration of Maintenance Therapy: most experts recommend at least 2 years of maintenance therapy
• Bactrim: decreases frequency of relapse, related to a reduction in nasal Staph aureus carriage
  • Whatever the case, Bactrim should be used for PCP prophylaxis (if not sulfa allergic) in patients on immumosuppressive regimens
• European Vasculitis Study Group Placebo-Controlled Trial of Nasal Mupirocin for the Prevention of Relapse (MUPIBAC Trial): in progress

Side Effects of Therapy

• Infection
  • 10% of cyclophosphamide-treated patients develop clinically important infection (even in the absence of cyclophosphamide-induced leukopenia)
  • Combined steroids + cyclophosphamide increase the risk over cyclophosphamide alone
• Cyclophosphamide-Specific Side Effects:
  • 12% of cyclophosphamide-treated patients develop cystitis
  • 8% of cyclophosphamide-treated patients develop myelodysplastic syndrome
  • 5% of cyclophosphamide-treated patients develop a solid malignancy

Relapse

• Prevalance of Relapse
  • 50% of all ANCA-associated vasculitis patients have at least one relapse, despite active treatment
  • Relapse occurs in 25-33% of Microscopic Polyangiitis cases (in contrast, occurs in 40-65% of Wegener’s Granulomatosis cases and 15-25% of Churg-Strauss cases)
• Site of Relapse: may be in an initially affected organ or in a new organ
• Treatment of Relapse: repeat induction

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References

• Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. N Engl J Med 2010; 363:221-232
• Pulmonary Capillaritis. The association with progressive airflow limitation and hyperinflation. Am Rev Resp Dis 1993; 148: 507-511