Antibody subtypes and titers predict clinical outcomes in ANCA-associated vasculitis

Abstract

The objective of this study is to evaluate the association between antineutrophil cytoplasmic autoantibody (ANCA) subtype and ANCA titers on clinical outcomes and disease activity among a cohort of patients from Central Appalachia diagnosed with ANCA-associated vasculitis (AAV) over a 3-decade period. This is a retrospective chart review of all patients diagnosed with AAV. ANCA subtypes (myeloperoxidase (MPO) and proteinase 3 (PR3)) and titers at the time of diagnosis and at the time of relapse or last follow-up were evaluated along with patient outcomes. Outcomes of interest included relapse, development of end-stage renal disease (ESRD) and mortality. Sensitivity analysis and multivariable analysis were performed. Of the 202 patients, 111 patients were MPO-ANCA positive and 91 patients were PR3-ANCA positive. Relapse was more frequent among patients with PR3-ANCA compared to MPO-ANCA (35% vs 12%, p < 0.001). In both ANCA subgroups, the strongest predictor of relapse was an increase in titers prior to relapse, HR 8.1 (95% CI 1.6–40), p 0.009. Patients who achieved serological remission had a lower risk of ESRD [sub-HR 0.31 (95% CI 0.11–0.89)] and mortality [HR (95% CI) 0.24 (0.07–0.7)]. PR3-ANCA was associated with higher risk of ESRD [sub-HR 3.1 (95% CI 1.1–8.5)]. There was no difference in mortality between patients with MPO-ANCA and PR3-ANCA. Our study supports the use of both ANCA subtypes and titer levels for predicting clinical outcomes in patients receiving treatment for AAV. Monitoring of ANCA antibody titers may be useful since both serological remission and increase in titers provide prognostic information.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Watts RA, Mahr A, Mohammad AJ, Gatenby P, Basu N, Flores-Suárez LF (2015) Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant 30(Suppl 1):14–22. https://doi.org/10.1093/ndt/gfv022

    CAS  Article  Google Scholar 

  2. 2.

    Davies DJ, Moran JE, Niall JF, Ryan GB (1982) Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 285:606. https://doi.org/10.1136/bmj.285.6342.606

    CAS  Article  Google Scholar 

  3. 3.

    Brix SR, Noriega M, Tennstedt P, Vettorazzi E, Busch M, Nitschke M et al (2018) Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int 94:1177–1188. https://doi.org/10.1016/j.kint.2018.07.020

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    van Daalen EE, Wester Trejo MAC, Göçeroğlu A, Ferrario F, Joh K, Noël LH et al (2020) Developments in the histopathological classification of ANCA-associated glomerulonephritis. Clin J Am SocNephrol 15:1103–1111. https://doi.org/10.2215/CJN.14561119

    Article  Google Scholar 

  5. 5.

    Hagen EC, Daha MR, Hermans J, Andrassy K, Csernok E, Gaskin G et al (1998) Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int 53:743–753. https://doi.org/10.1046/j.1523-1755.1998.00807.x

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Craven A, Robson J, Ponte C, Grayson PC, Suppiah R, Judge A et al (2013) ACR/EULAR-endorsed study to develop Diagnostic and Classification Criteria for Vasculitis (DCVAS). ClinExpNephrol 17:619–621. https://doi.org/10.1007/s10157-013-0854-0

    CAS  Article  Google Scholar 

  7. 7.

    Kallenberg CG (2010) Pathophysiology of ANCA-associated small vessel vasculitis. CurrRheumatol Rep 12:399–405. https://doi.org/10.1007/s11926-010-0138-6

    CAS  Article  Google Scholar 

  8. 8.

    Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O et al (2012) Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis 71:955–960. https://doi.org/10.1136/annrheumdis-2011-200477

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Group WsGETWR (2005) Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351–361. https://doi.org/10.1056/NEJMoa041884

    Article  Google Scholar 

  10. 10.

    Boomsma MM, Stegeman CA, van der Leij MJ, Oost W, Hermans J, Kallenberg CG et al (2000) Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 43:2025–2033. https://doi.org/10.1002/1529-0131(200009)43:9%3c2025::AID-ANR13%3e3.0.CO;2-O

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Sanders JS, Huitma MG, Kallenberg CG, Stegeman CA (2006) Prediction of relapses in PR3-ANCA-associated vasculitis by assessing responses of ANCAtitres to treatment. Rheumatology (Oxford) 45:724–729. https://doi.org/10.1093/rheumatology/kei272

    CAS  Article  Google Scholar 

  12. 12.

    Terrier B, Saadoun D, Sène D, Ghillani P, Amoura Z, Deray G et al (2009) Antimyeloperoxidase antibodies are a useful marker of disease activity in antineutrophil cytoplasmic antibody-associated vasculitides. Ann Rheum Dis 68:1564–1571. https://doi.org/10.1136/ard.2008.094714

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Watanabe H, Sada KE, Matsumoto Y, Harigai M, Amano K, Dobashi H et al (2018) Association between reappearance of myeloperoxidase-antineutrophil cytoplasmic antibody and relapse in antineutrophil cytoplasmic antibody-associated vasculitis: subgroup analysis of nationwide prospective cohort studies. Arthritis Rheumatol 70:1626–1633. https://doi.org/10.1002/art.40538

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kemna MJ, Damoiseaux J, Austen J, Winkens B, Peters J, van Paassen P et al (2015) ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am SocNephrol 26:537–542. https://doi.org/10.1681/ASN.2013111233

    CAS  Article  Google Scholar 

  15. 15.

    Finkielman JD, Merkel PA, Schroeder D, Hoffman GS, Spiera R, St Clair EW et al (2007) Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med 147:611–619. https://doi.org/10.7326/0003-4819-147-9-200711060-00005

    Article  PubMed  Google Scholar 

  16. 16.

    Nowack R, Grab I, Flores-Suarèz LF, Schnülle P, Yard B, van der Woude FJ (2001) ANCAtitres, even of IgG subclasses, and soluble CD14 fail to predict relapses in patients with ANCA-associated vasculitis. Nephrol Dial Transplant 16:1631–1637. https://doi.org/10.1093/ndt/16.8.1631

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kyndt X, Reumaux D, Bridoux F, Tribout B, Bataille P, Hachulla E et al (1999) Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis. Am J Med 106:527–533. https://doi.org/10.1016/s0002-9343(99)00064-9

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Tomasson G, Grayson PC, Mahr AD, Lavalley M, Merkel PA (2012) Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis—a meta-analysis. Rheumatology (Oxford) 51:100–109. https://doi.org/10.1093/rheumatology/ker280

    CAS  Article  Google Scholar 

  19. 19.

    Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F et al (2013) 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65:1–11. https://doi.org/10.1002/art.37715

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP et al (1990) The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 33:1101–1107. https://doi.org/10.1002/art.1780330807

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W et al (2007) Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 66:222–227. https://doi.org/10.1136/ard.2006.054593

    Article  PubMed  Google Scholar 

  22. 22.

    Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K et al (2011) The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 80:17–28. https://doi.org/10.1038/ki.2010.483

    Article  PubMed  Google Scholar 

  23. 23.

    Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA et al (2014) KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 63:713–735. https://doi.org/10.1053/j.ajkd.2014.01.416

    Article  PubMed  Google Scholar 

  24. 24.

    Hilhorst M, van Paassen P, Tervaert JW, Registry LR (2015) Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J Am SocNephrol 26:2314–2327. https://doi.org/10.1681/ASN.2014090903

    CAS  Article  Google Scholar 

  25. 25.

    Berti A, Cornec-Le Gall E, Cornec D, Casal Moura M, Matteson EL, Crowson CS et al (2019) Incidence, prevalence, mortality and chronic renal damage of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a 20-year population-based cohort. Nephrol Dial Transplant 34:1508–1517. https://doi.org/10.1093/ndt/gfy250

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Hogan SL, Falk RJ, Chin H, Cai J, Jennette CE, Jennette JC et al (2005) Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 143:621–631. https://doi.org/10.7326/0003-4819-143-9-200511010-00005

    Article  PubMed  Google Scholar 

  27. 27.

    Weidner S, Geuss S, Hafezi-Rachti S, Wonka A, Rupprecht HD (2004) ANCA-associated vasculitis with renal involvement: an outcome analysis. Nephrol Dial Transplant 19:1403–1411. https://doi.org/10.1093/ndt/gfh161

    Article  PubMed  Google Scholar 

  28. 28.

    Mohammad AJ, Segelmark M (2014) A population-based study showing better renal prognosis for proteinase 3 antineutrophil cytoplasmic antibody (ANCA)-associated nephritis versus myeloperoxidase ANCA-associated nephritis. J Rheumatol 41:1366–1373. https://doi.org/10.3899/jrheum.131038

    Article  PubMed  Google Scholar 

  29. 29.

    de Joode AA, Sanders JS, Stegeman CA (2013) Renal survival in proteinase 3 and myeloperoxidase ANCA-associated systemic vasculitis. Clin J Am SocNephrol 8:1709–1717. https://doi.org/10.2215/CJN.01020113

    CAS  Article  Google Scholar 

  30. 30.

    Berti A, Cornec D, Crowson CS, Specks U, Matteson EL (2017) The epidemiology of antineutrophil cytoplasmic autoantibody-associated vasculitis in Olmsted county, Minnesota: a 20-year US population-based study. Arthritis Rheumatol 69:2338–2350. https://doi.org/10.1002/art.40313

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Solans-Laqué R, Fraile G, Rodriguez-Carballeira M, Caminal L, Castillo MJ, Martínez-Valle F et al (2017) Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides: impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity. Medicine (Baltimore) 96:e6083. https://doi.org/10.1097/MD.0000000000006083

    Article  Google Scholar 

  32. 32.

    Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS (1993) Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener’s granulomatosis. Arthritis Rheum 36:365–371. https://doi.org/10.1002/art.1780360312

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    He P, Hu J-P, Tian X-J, He L-J, Sun S-R, Huang C (2020) Prevalence and risk factors of relapse in patients with ANCA-associated vasculitis receiving cyclophosphamide induction: a systematic review and meta-analysis of large observational studies. Rheumatology. https://doi.org/10.1093/rheumatology/keaa667

    Article  PubMed  Google Scholar 

Download references

Funding

None.

Author information

Affiliations

Authors

Contributions

MA: conducted the literature search for the background of the study, collected, analyzed and interpreted statistical data, wrote the majority of the manuscript; DM: contributed to the design and data collection, the analysis of the results and the writing of the manuscript; AH: contributed to the data collection; JT: contributed to the design, analysis of results and interpreting statistical data; BP and RS: contributed to the analysis of the results and the writing of the manuscript; KS: contributed to the data collection, analyzed, interpreted statistical data and writing of the manuscript; DK: contributed to the design of the study, the collection of data, analysis of the results and the writing of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Dinesh Kannabhiran.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Investigation Committee (IRB) of West Virginia University approved this study. IRB approval number: 1905572870.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aljuhani, M., Makati, D., Hoff, A. et al. Antibody subtypes and titers predict clinical outcomes in ANCA-associated vasculitis. Rheumatol Int (2021). https://doi.org/10.1007/s00296-021-04802-w

Download citation

Keywords

  • ANCA-associated vasculitis
  • Clinical outcomes
  • End-stage renal disease
  • Relapse
  • Mortality
  • ANCA subtypes
  • ANCA titers
  • Serological remission