Introduction
ANCA (antineutrophil cytoplasmic antibodies) are host-derived autoantibodies directed against neutrophils recruited by the immune system. There are two types of ANCAs: pANCA and cANCA. ANCA is seen in certain inflammatory autoimmune disorders of the blood vessels like granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss syndrome), and polyarteritis nodosa.
What Is the Pathophysiology of ANCA-mediated Autoimmunity?
Neutrophils contain multitudes of proteins out of which myeloperoxidase and proteinase-3, present in azurophilic granules, are clinically significant to ANCA-mediated vasculitis. Autoantibody formation is triggered by various factors like microbial infection, genetic factors, environmental agents, and therapeutic drugs. The factors produce proinflammatory cytokines that prime a sufficient amount of neutrophils resulting in the exposure of cytoplasmic proteins (myeloperoxidase and proteinase-3) on the surface of the neutrophils. The affected neutrophils migrate, attach, and accumulate within the vessels over the endothelium. Degranulation leads to apoptosis of the neutrophils and the release of reactive oxygen radicals that cause epithelial cell damage. The injury leads to leakage of serum proteins and coagulation factors that causes fibrinoid necrosis. The inflammatory process is accelerated by ANCAs produced by B-cells, neutrophil abnormalities, T-cell subtype imbalance, and excess of Th17 helper cells.
Who Are Indicated for Plasma Exchange Therapy?
Plasma exchange therapy is indicated in patients with:
-
Serum creatinine of more than 5.7 MG/Dl.
-
Granulomatosis with polyangiitis (GPA).
-
Microscopic polyangiitis (MPA).
-
Eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss syndrome).
-
Polyarteritis nodosa.
-
Gbs (Guillain-barré syndrome).
-
Chronic inflammatory demyelinating polyneuropathy.
-
MG (Myasthenia gravis).
-
Hyperviscosity syndrome.
-
Thrombotic thrombocytopenic purpura.
-
Hemolytic uremic syndrome.
-
Idiopathic thrombocytopenia.
-
Renal diseases.
-
Rheumatologic diseases.
What Is the Pathogenetic Rationale for Plasma Exchange in ANCA-Associated Vasculitis?
ANCA are constitutionally IgG antibodies, as detected with IF and ELISA, with two primary targets- MPO and PR3 which are found in neutrophils and monocytes. The hypothesis of ANCA-associated vasculitis states that ANVA binding to primed neutrophils leads to its degranulation and activation of complement pathways after accumulation over the endothelium. Several studies have also reported direct pathogenicity of ANCA to vasculitis.
Studies have shown:
-
Infusion of splenocytes from immunized MPO mice or purified anti-MPO IgG antibodies into normal mice resulted in the development of severe necrotizing and crescentic glomerulonephritis.
-
Rats infused with human MPO developed crescentic glomerulonephritis and lung hemorrhage.
-
Placental transfer of MPO antibodies from a mother to the fetus in humans led to lung hemorrhage in the neonate.
This established a direct relationship between ANCA and vascular inflammation leading to the hypothesis stating the removal of ANCA might exert a beneficial effect on the pathological state. IgG has a half-life of 21 days, so immunosuppressive therapy would require weeks of administration to induce remission. On the other hand, plasm exchange offered a rapid removal of ANCA antibodies in combination with immunosuppressive therapy. Due to the extravascular distribution of IgG, plasma exchange is performed on alternative days in order to allow IgGs to further redistribute into the vascular space on the gap day. Plasma exchange also removes inflammatory mediators like cytokines and complement components and replenishes plasma factors via fresh frozen plasma infusion like factor H.
What Are the Current Clinical Indications for Plasma Exchange in ANCA-Associated Vasculitis?
ANCA-associated vasculitis affects small vessels and leads to multiple organ failures, especially kidneys and lungs. The kidney is the most commonly affected organ in GPA and MPA cases which has a great prognostic value to determine patient survival. An estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2 correlates to end-stage kidney disease and 5-year mortality. Kidney disorder reflects as necrotizing crescentic glomerulonephritis with a rapid decline in kidney function with proteinuria and active urine sediment. Lung involvement reflects a diffuse alveolar hemorrhage with an increased risk of death. Traditional therapies included immunosuppressants with corticosteroid therapy but were susceptible to superinfections and malignancies.
The use of plasma exchange is currently reserved for patients with severe renal impairment or lung hemorrhage. Plasma exchange should be considered in patients with serum creatinine levels above 5.7 mg/dL, requiring dialysis or with a rapidly increasing creatinine, and in patients with diffuse alveolar hemorrhage and hypoxemia.
Plasma exchange is also indicated in overlap syndrome where ANCA-associated vasculitis coexists with anti-GBM antibodies presenting with severe acute glomerulonephritis and lung hemorrhage. Plasma exchange therapy is indicated in patients with linear IgG deposition along the glomerular basement membrane in kidney biopsy or diffuse alveolar hemorrhage until circulating anti-GBM antibodies are no longer detected.
What Was the MEPEX Trial?
The MEPEX trial was published in 2007 that compared the effectiveness of adjunct plasma exchange therapy versus pulses of intravenous Methylprednisolone in patients presenting with severe renal involvement.
The use of plasma therapy resulted in significant improvement in renal recovery at 3 months in 69% of the patients as compared to 49% in the Methylprednisolone group. Plasma exchange also demonstrates a 24% reduction in end-stage kidney disease (ESKD) and death as compared to the IV-Methylprednisolone group. MEPEX trial supported the hypothesis of increased effectiveness of plasma exchange over traditional pharmacotherapy but only over a short period. A four-year follow-up showed ESKD or death occurred in 68% of the patients, a similar outcome in both groups.
Another analysis underlined a favorable effect of TPE on ESKD but not on mortality. Yet another study added plasma exchange to standard immunosuppressive therapy in PR3-ANCA-positive patients and that improved the composite primary outcome of death, ESKD, and relapses at 1-year evaluation. The latest MEPEX trial reported that the addition of plasma exchange to the standard induction regimen did not benefit remission at 6 months or the incidence of ESKD and patient survival at 18 and 24 months.
What Was the PEXIVAS Trial?
The PEXIVAS trial studied plasma exchange therapy outcomes in patients who present with severe AAV(eGFR < 50 mL/min/1.73m2) or diffuse alveolar hemorrhage. The trial focused on two factors, first was an initial treatment with seven sessions of plasma exchange within 14 days or no plasma exchange and a standard-dose glucocorticoid regimen versus a reduced-dose regimen.
Patients with plasma exchange reported ESKD or death in 28.4% in the plasma exchange group and 31% in the control group after a median follow-up of 2.9 years. There was no significant difference in the secondary outcomes of ESKD, death from any cause, sustained remission, serious adverse events, and serious infections at 1 year between the two groups. The low-dose corticosteroid group showed significantly fewer serious infections at 1-year follow-up.
Conclusion
The usage of plasma exchange after the PEXIVAS trial created huge controversies regarding its effectiveness as it showed non-significant improvement over the second group. Yet the trial provided concrete evidence of a lower dosage of corticosteroids is effective in preventing infections. Despite the outcome, plasma exchange may still have a role in the management of this life-threatening complication as more evidence from PEXIVAS will emerge in the future. Until more clinical studies show concrete consequences, plasma exchange continues to be a therapeutic option in patients with ANCA-associated vasculitis.
