Case 18: Diagnosis & Conclusion

Case 18 Index

Diagnosis: Granulomatosis with Polyangiitis (GPA, formerly Wegener’s disease)

Case Summary: 

Great learning case! Let’s break it down, starting from the HPI. We meet a 40 year-old woman with acute on chronic respiratory symptoms and a purpuric rash with toe ischemia. Our broad differential includes an inflammatory, vasculitic, or embolic process. Initial laboratory assessment is notable for acute kidney injury with sub-nephrotic range proteinuria, hematuria, and red blood cell casts on urine microscopy. Together, this suggests an acute nephritic syndrome and a rapidly progressive glomerulonephritis (RPGN).

Classification of RPGN
Anti-glomerular basement membrane disease
Also known as Goodpasture’s disease; typically affects the small vessels of the kidney and lung and can be diagnosed by biopsy and an elevated anti-GBM antibody titer.
Immune-complex mediated
Can be secondary to wide variety of immune-complex mediated disease (i.e. systemic lupus erythematosus (SLE), hepatitis C virus, IgA nephropathy, post-infectious glomerulonephritis)
Pauci-immune
Usually anti-neutrophil cytoplasmic antibody (ANCA) associated, and named because of the absence of immune complex deposition (absence of deposits on electron microscopy and negative immunofluorescence)

With our working differential for RPGN, we now utilize serologic testing and ultimately the kidney biopsy to make the diagnosis. In this case we find normal complement levels, normal ANA, anti-double stranded DNA, and  undetectable cryoglobulins – these data make immune-complex mediated disease less likely. also make. Thus, we are left with RPGN that is either pauci-immune or anti-GBM disease.

In a patient with RPGN, strongly positive c-ANCA titers (antibody against proteinase-with a cytoplasmic staining pattern) on the background of sinusitis and epistaxis lead us towards ANCA-associated vasculitis. C-ANCA is more commonly associated with Granulomatosis with Polyangiitis (GPA). What about that other ANCA? The presence of p-ANCA (antibody against myeloperoxidase with a perinuclear staining pattern) is more commonly associated with eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis.

If our diagnosis is correct, histology show us crescentic necrotizing glomerulonephritis and medullary angiitis– which it does! We also see obliteration of the capillary loops and endothelial cell proliferation. Neutrophils are also visible within the capillary loops and in the medullary interstitial space. The clincher for this diagnosis is the negative immunofluorescence (IF). We don’t get the electron microscopy (EM) for this case, but we would not expect to see any deposits.

The clinical presentation of GPA is diverse, but classic findings include upper respiratory tract symptoms, epistaxis, hemoptysis (due to diffuse alveoloar hemorrhage), and rapidly progressive renal failure (think: pulmonary-renal syndrome). Leukocytoclastic vasculitis in the skin can be seen as well. Although GPA is associated with “pauci-immune” lesions at the level of the glomerulus, detection of immune deposits in early skin lesions can be seen with active disease.

Pulmonary-Renal Syndromes (click below for clues on where to look for them!)
Primary systemic vasculitis
Granulomatosis with polyangiitis (c-ANCA, against proteinase-3) or microscopic polyangiitis (p-ANCA, against myeloperoxidase)
Goodpasture’s or anti-GBM disease
Antibodies most commonly against α3 chain of type IV collagen of glomerular and alveolar basement membranes
Systemic lupus erythematosus (SLE)
Presence of anti-nuclear antibody (ANA) and anti-double stranded DNA antibodies

Treatment for GPA: induction cyclophosphamide (IV or oral, CYCLOPS trial) or Rituximab (RAVE, RITUXVAS trials: rituxmab noninferior to CYC) with glucocorticoids. First choice for maintenance therapy remains azathioprine (CYCAZAREM trial). Diffuse pulmonary hemorrhage is an indication for plasmapheresis in combination with induction therapy, though the benefit of plasma exchange continues to be reassessed in on-going trials. Don’t forget the new kid on the block, avacopan, the C5a receptor antagonist that has shown some efficacy and potential to decrease steroid dosing.

Check out these references for more:

  1. Jennette JC, Nachman PH: ANCA Glomerulonephritis and Vasculitis. Clin. J. Am. Soc. Nephrol. CJASN 12: 1680–1691, 2017
  2. Schönermarck U, Gross WL, Groot K de: Treatment of ANCA-associated vasculitis. Nat. Rev. Nephrol. 10: 25–36, 2014
  3. Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, Burst V, Grundmann F, Jadoul M, Szombati I, Tesař V, Segelmark M, Potarca A, Schall TJ, Bekker P, Group for the CS: Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J. Am. Soc. Nephrol. ASN.2016111179, 2017

Case 18 Index
Case 18 Introduction
Case 18 Physical Exam

Case 18 Diagnostic Testing

Case 18 Pathology
Case 18 Additional Pathology
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