Microscopic Polyangiitis and Pauci-immune Glomerulonephritis Scott McCord, PGY3

Vasculitis Classification Large vessel vasculitis Takayasu arteritis Giant cell (temporal) arteritis Medium vessel vasculitis Polyarteritis nodosa Kawasaki disease Primary CNS vasculitis Small vessel vasculitis ANCA-associated Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Granulomatosis with polyangiitis (Wegener’s) Microscopic polyangiitis Renal-limited vasculitis Immune-complex mediated Henoch-Schönlein purpura (IgA vasculitis) Cryoglobulinemic vasculitis Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) Anti-GBM antibody disease

Distribution of vessel involvement by large, medium, and small vessel vasculitis

C-ANCA/P-ANCA ANCA = Antineutrophil cytoplasmic antibodies C-ANCA/P-ANCA are immunofluorescence patterns on an indirect immunofluorescence assay, using alcohol-fixed buffy coat leukocytes Screening test only, positivity is subjective, not measuring quantity or titer of an antibody “C” for cytoplasm “P” for peri-nuclear

Proteinase 3 (PR3) and Myeloperoxidase (MPO) These are the two relevant target antigens for the ANCA’s Tested for by enzyme-linked immunosorbent assay (ELISA), using purified specific antigens Send-out test to reference lab, will also have a quantity/titer of antibody if positive PR3 – lives in azurophilic granules in cytoplasm, hence association with C-ANCA pattern MPO – also lives in azurophilic granules, but becomes positively charged when fixated with ethanol, migrates to negatively charged nuclear membrane, leading to peri-nuclear fluorescence (P-ANCA pattern) ELISA for PR3 and MPO is a highly specific and sensitive test, used to confirm a positive C-ANCA or P-ANCA. Order both if either pattern is positive, as they can overlap

P-ANCA/MPO Vasculitis Can present as EGPA, GPA, MPA, or renal-limited vasculitis GPA – usually C-ANCA/PR3, but can be P-ANCA/MPO, presents with widespread involvement usually including both lungs and kidneys, more malignant course than MPA MPA – usually P-ANCA/MPO, can have widespread involvement as well, but more likely to have renal involvement than pulmonary involvement, less likely to relapse after treatment Renal-limited vasculitis – usually P-ANCA/MPO, initially presents with only renal involvement, can progress to extra renal manifestations

Pauci-immune glomerulonephritis The glomerulonephritis associated with all 4 of these ANCA vasculitides Glomerulonephritis associated with few or no immune deposits in the glomeruli on immunofluorescence and electron microscopy (hence, paucity) Severity ranges from mild focal and segmental glomerulonephritis in patients with asymptomatic hematuria and normal or near-normal renal function to a diffuse necrotizing and crescentic glomerulonephritis in patients with acute kidney injury Typically occurs in association with involvement of other organs in both GPA and MPA, some patients present with a renal-limited, ANCA-positive vasculitis (usually P-ANCA/MPO)

Initial Treatment of GPA/MPA Mild disease – no evidence of active glomerulonephritis or other organ-threatening manifestations Start with prednisone + methotrexate Moderate/severe disease – pulmonary hemorrhage or deteriorating renal function Start with prednisone + cyclophosphamide/rituximab Also for either group, start PJP prophylaxis at time of initiating immunosuppression – bactrim or atovaquone