• 1.

    Jerke U, et al. Targeting cathepsin C in PR3-ANCA vasculitis. J Am Soc Nephrol 2022; 33:936947. doi: 10.1681/ASN.2021081112

  • 2.

    Rhee RL, et al. Trends in long-term outcomes among patients with antineutrophil cytoplasmic antibody-associated vasculitis with renal disease. Arthritis Rheumatol 2016; 68:17111720. doi: 10.1002/art.39614

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Wallace ZS, et al. Nationwide trends in hospitalizations and in-hospital mortality in granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 2017; 69:915921. doi: 10.1002/acr.22976

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Mohammad AJ, et al. Severe infection in antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol 2017; 44:14681475. doi: 10.3899/jrheum.160909

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Charlier C, et al. Risk factors for major infections in Wegener granulomatosis: Analysis of 113 patients. Ann Rheum Dis 2009; 68:658663. doi: 10.1136/ard.2008.088302

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Goupil R, et al. Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol 2013; 8:416423. doi: 10.2215/CJN.07300712

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Jayne DRW, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021; 384:599609. doi: 10.1056/NEJMoa2023386

Assessment of Cathepsin C Inhibition as an Effective Treatment for Anti-PR3 Antibody ANCA-Associated Vasculitis

Suneel M. UdaniSuneel M. Udani, MD, FASN, is with Nephrology Associates of Northern Illinois and Indiana, Oak Brook, IL.

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Can targeting the cathepsin C (CatC) in proteinase-3 (PR3)-anti-neutrophil cytoplasmic antibody (ANCA) vasculitis prevent the inflammatory injury associated with ANCA-associated vasculitis (AAV) (1)? Recognizing that neutrophils from individuals with a loss-of-function mutation in a non-serine protease—CatC—maintain bactericidal activity but have limited ANCA reactivity, the authors of a recent study propose pharmacologic inhibition of CatC as a therapeutic target for anti-PR3 antibody (anti-PR3 Ab) AAV (1).

Genetic CatC deficiency is associated with the autosomal recessive condition known as Papillon-Lefèvre syndrome (PLS). After previously noting that mice with CatC deficiency were protected from AAV, the authors designed a study to assess whether human neutrophils from those with PLS would similarly be protected from ANCA-immunoglobulin (Ig) activation and subsequent endothelial injury. Neutrophils from healthy controls (HCs) and individuals with PLS were incubated with endothelial cells and exposed to ANCA-Ig. Antibody deposition, indicators of neutrophil activation (e.g., generation of reactive oxygen species), and degree of endothelial cell injury were assessed. Neutrophils from those with PLS had negative immunofluorescence, less neutrophil activation, and less endothelial cell injury. To assess the impact of pharmacologic CatC inhibition, hematopoietic stem cells that differentiated into neutrophils from HCs were exposed to ANCA-Ig with and without a pharmacologic inhibitor of CatC. Neutrophils treated with CatC inhibition demonstrated similar outcomes as did individuals with PLS—less neutrophil activation and less endothelial injury. Ultimately, the authors concluded that a pharmacologic inhibitor of CatC prevented AAV-associated neutrophil activation and endothelial cell injury (1).

AAV is a life-threatening disease with a mortality of greater than 90% if untreated (2). Accordingly, the need for effective therapy to prevent the severe complications of the disease is self-evident. Although the current therapeutic approach effectively induces remission in greater than 60% of individuals, it remains associated with significant toxicity of prolonged impaired humoral immunity (3). An estimated 25% to 30% of patients with AAV will develop infection—significantly higher than a comparable population without AAV (4, 5). Furthermore, lymphopenia associated with induction treatment is strongly correlated with risk of serious and non-serious infection (6).

Induction therapeutic strategies to prevent organ injury with minimal systemic immunosuppression are needed. Furthermore, anti-PR3 Ab AAV remains a high risk for relapse after remission; therefore, clinical management must include a safe, reliable option for long-term use. The recent experience with the C5a inhibitor avacopan provides insight into the potential benefits of targeted therapy in AAV. When glucocorticoids were minimized in favor of avacopan, the risk of serious and non-serious infections fell without a reduction in therapeutic efficacy (7).

Ultimately, if CatC inhibition proves to be an effective treatment for anti-PR3 Ab AAV, and similar targets can be identified for both anti-PR3 Ab AAV and anti-myeloperoxidase Ab AAV, then the balance between effective therapeutic intervention and complications of treatment can move even more favorably toward optimizing patient outcomes.

References

  • 1.

    Jerke U, et al. Targeting cathepsin C in PR3-ANCA vasculitis. J Am Soc Nephrol 2022; 33:936947. doi: 10.1681/ASN.2021081112

  • 2.

    Rhee RL, et al. Trends in long-term outcomes among patients with antineutrophil cytoplasmic antibody-associated vasculitis with renal disease. Arthritis Rheumatol 2016; 68:17111720. doi: 10.1002/art.39614

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Wallace ZS, et al. Nationwide trends in hospitalizations and in-hospital mortality in granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 2017; 69:915921. doi: 10.1002/acr.22976

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Mohammad AJ, et al. Severe infection in antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol 2017; 44:14681475. doi: 10.3899/jrheum.160909

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Charlier C, et al. Risk factors for major infections in Wegener granulomatosis: Analysis of 113 patients. Ann Rheum Dis 2009; 68:658663. doi: 10.1136/ard.2008.088302

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Goupil R, et al. Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol 2013; 8:416423. doi: 10.2215/CJN.07300712

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Jayne DRW, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021; 384:599609. doi: 10.1056/NEJMoa2023386

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