Microscopic Polyangiitis (MPA) - MD Examination Answer

1. Definition and Classification

• Necrotizing vasculitis with few or no immune deposits (pauci-immune)
• Absence of granulomatous inflammation (this is the key feature distinguishing MPA from GPA)
• Predilection for small vessels
• Fishman's Pulmonary Diseases and Disorders, Chapter 74

2. Epidemiology

• Annual incidence: approximately 2.7 per million (varies by geographic region)
• MPA is the most frequent cause of pulmonary-renal syndrome
• Slightly more common in males; peak onset in the 5th-7th decades
• Fishman's, Chapter 74

3. Pathogenesis

ANCA-Mediated Mechanism

• Respiratory burst (reactive oxygen species production)
• Degranulation (release of proteolytic enzymes)
• Neutrophil extracellular trap (NET) formation
• Endothelial damage and vessel wall inflammation

• Genome-wide association studies show MPA is genetically distinct from GPA
• Strongest genetic associations are based on ANCA specificity (MPO-ANCA vs. PR3-ANCA) rather than clinical syndrome
• MPO-ANCA patients associate with HLA-DQ
• Epigenetic modifications interfere with normal silencing of genes coding for MPO in mature neutrophils
• Fishman's, Chapter 74 (Pathophysiology of ANCA-Associated Vasculitis)

4. Pathology

• Focal segmental necrotizing crescentic glomerulonephritis - the most consistent pathologic feature
• Pauci-immune pattern - little or no immunoglobulin deposition on immunofluorescence (distinguishes from immune complex GN)
• Extracapillary proliferation forming crescents
• Absent granulomas - key distinction from GPA
• Lesions tend to be of the same age in any given patient (unlike PAN, where lesions are of varying ages)

• Pulmonary capillaritis - neutrophilic infiltration of alveolar walls
• Diffuse Alveolar Hemorrhage (DAH) - histologically indistinguishable from GPA capillaritis
• Transition to pulmonary fibrosis with restrictive ventilatory impairment after recurrent episodes (more so than GPA)

• Murray & Nadel's, Chapter 87; Fishman's, Chapter 74

5. Clinical Features

Constitutional Symptoms

Renal (most common - up to 80% of patients)

• Rapidly progressive glomerulonephritis (RPGN) - most feared complication
• Hematuria, proteinuria, red cell casts
• Acute kidney injury progressing to ESRD if untreated

Pulmonary (10-30% of patients)

• Diffuse Alveolar Hemorrhage (DAH) due to pulmonary capillaritis
• Hemoptysis (may be absent in up to 1/3 of cases)
• Dyspnea, hypoxemia
• The alveolar hemorrhage tends to be severe and often life-threatening
• Association with interstitial lung disease (ILD) - particularly UIP and NSIP patterns, especially with MPO-ANCA
• Several cases describe association with bronchiectasis and severe obstructive airways disease
• MPA is the most frequent cause of pulmonary-renal syndrome

Skin

• Palpable purpura due to leukocytoclastic vasculitis (most common cutaneous finding)

Musculoskeletal

• Arthralgias, myalgias

Gastrointestinal (about 1/3 of patients)

• Diarrhea, gastrointestinal bleeding from mucosal vasculitis
• Visceral angiography generally not helpful (vessels too small to visualize)
• CT preferred for evaluation

Nervous System

• Peripheral neuropathy (mononeuritis multiplex)

Important Negative Features (MPA vs. GPA vs. EGPA)

• Sinusitis and upper airway disease are rare in MPA; their presence suggests GPA
• Asthma is absent; its presence suggests EGPA
• No granulomatous inflammation
• Fishman's, Chapter 74; Murray & Nadel's, Chapter 87

6. Laboratory Investigations

• Murray & Nadel's, Chapter 87

7. Diagnosis

1. Clinical syndrome consistent with small vessel vasculitis (renal, pulmonary, skin involvement)
2. ANCA positivity (P-ANCA/MPO-ANCA in most cases)
3. Tissue biopsy - from the most accessible site:
   • Renal biopsy: pauci-immune necrotizing crescentic glomerulonephritis without granulomas
   • Skin biopsy: leukocytoclastic vasculitis
   • Lung: capillaritis on transbronchial or surgical biopsy
4. Exclusion of granulomatous inflammation (to distinguish from GPA)

• Fishman's, Chapter 74

8. Treatment

Goals of Therapy

1. Induce remission as quickly as possible to minimize irreversible organ damage
2. Maintain remission with minimal treatment-related toxicity

Remission Induction (for Severe/Organ-Threatening Disease)

• Rituximab (four doses of 375 mg/m²) OR cyclophosphamide + high-dose glucocorticoids
• Rituximab has been shown non-inferior to cyclophosphamide for remission induction (RAVE and RITUXVAS trials)
• Rituximab preferred in: younger patients (fertility preservation), relapsing disease, cyclophosphamide-intolerant patients

• Recommended for MPA with hypoxemic respiratory failure (DAH) or renal failure
• Large RCT (PEXIVAS) did not show benefit for renal outcomes, but PLEX remains a mainstay for ANCA-associated DAH
• In uncontrolled DAH: IV Factor VIIa has been used in isolated cases

Remission Maintenance

• Rituximab (preferred) - repeated doses every 6 months
• Azathioprine (1-2 mg/kg/day) - alternative
• Mycophenolate mofetil - alternative, less commonly used
• Low-dose oral glucocorticoids during maintenance phase
• Duration: minimum 24 months; prolonged therapy may be required

Prophylaxis

• PCP prophylaxis: Trimethoprim-sulfamethoxazole (for all patients on immunosuppression; use other agents if sulfa-allergic)
• Folic acid 1 mg/day (if on methotrexate)
• Osteoporosis prophylaxis: Calcium + Vitamin D + bisphosphonates (all patients on glucocorticoids)
• Antifungal prophylaxis during intense induction phase

ILD and MPA (Special Situation)

• Active MPA + ILD: Standard severe MPA immunosuppression (glucocorticoids + cyclophosphamide or rituximab)
• MPO-ANCA + NSIP/inflammatory ILD without vasculitis: Trial of glucocorticoids + azathioprine or MMF
• MPO-ANCA + UIP pattern without vasculitis: Do NOT give immunosuppression (increases mortality) - offer antifibrotic therapy instead
• Fishman's, Chapter 74; Murray & Nadel's, Chapter 87

9. Prognosis

• With early initiation of therapy: 65% rate of 5-year survival (Murray & Nadel's)
• DAH contributes to early mortality rate of 25%
• Tendency to recurrence with tapering of medications
• Recurrent alveolar hemorrhage leads to transition to pulmonary fibrosis and restrictive ventilatory impairment
• Disease activity monitored by: ESR, ANCA levels, serial DLCO, microscopic urine examination

10. Key Distinguishing Features

Summary Points for Exam

1. MPA = ANCA-associated vasculitis; pauci-immune, no granulomas, small vessels
2. P-ANCA/MPO-ANCA in 40-80%; C-ANCA less common (if present, consider reclassification to GPA later)
3. Kidneys (80%) and lungs (10-30% as DAH) are the main targets
4. Most common cause of pulmonary-renal syndrome
5. Pathology: focal segmental necrotizing crescentic GN (pauci-immune); pulmonary capillaritis
6. All lesions same age (unlike PAN)
7. Sinusitis/asthma absent - their presence shifts diagnosis toward GPA/EGPA
8. Treatment: rituximab or cyclophosphamide + steroids for induction; rituximab or azathioprine for maintenance
9. PLEX for DAH with respiratory failure; avacopan as steroid-sparing option
10. UIP + MPO-ANCA without vasculitis = antifibrotic, not immunosuppression
11. Prognosis: 65% 5-year survival; 25% early mortality with DAH